Methods of use of diazacarbazoles for treating cancer

ABSTRACT

Methods of use of compounds of formula (I) for treating cancer: 
     
       
         
         
             
             
         
       
     
     wherein X, Y, X, R 3 , R 5  and R 6  are as defined herein.

This application claims the benefit of U.S. Provisional Application No.61/060,746, filed Jun. 11, 2008 and U.S. Provisional Application No.61/148,001, filed Jan. 28, 2009, the disclosure of both are incorporatedherein by reference in their entirety.

The invention relates to 1,7-diazacarbazole compounds which are usefulas kinase inhibitors, more specifically useful as checkpoint kinase 1(chk1) inhibitors, thus useful as cancer therapeutics. The inventionalso relates to compositions, more specifically pharmaceuticalcompositions comprising these compounds and methods of using the same totreat various forms of cancer and hyperproliferative disorders, as wellas methods of using the compounds for in vitro, in situ, and in vivodiagnosis or treatment of mammalian cells, or associated pathologicalconditions.

Individual cells replicate by making an exact copy of their chromosomes,and then segregating these into separate cells. This cycle of DNAreplication, chromosome separation and division is regulated bymechanisms within the cell that maintain the order of the steps andensure that each step is precisely carried out. Involved in theseprocesses are the cell cycle checkpoints (Hartwell et al., Science, Nov.3, 1989, 246(4930):629-34) where cells may arrest to ensure DNA repairmechanisms have time to operate prior to continuing through the cycleinto mitosis. There are two such checkpoints in the cell cycle—the G1/Scheckpoint that is regulated by p53 and the G2/M checkpoint that ismonitored by the serine/threonine kinase checkpoint kinase 1 (chk1).

Chk1 and chk2 are structurally unrelated yet functionally overlappingserine/threonine kinases activated in response to genotoxic stimuli(reviewed in Bartek et al., Nat. Rev. Mol. Cell. Biol. 2001, vol. 2, pp.877-886). Chk1 and chk2 relay the checkpoint signals from the ATM andATR, which phosphorylate and activate them. Chk2 is a stable proteinexpressed throughout the cell cycle, activated mainly by ATM in responseto double-strand DNA breaks (DSBs). In contrast, Chk1 protein expressionis largely restricted to S and G2 phases. In response to DNA damage,ChK1 is phosphorylated and activated by ATM/ATR, resulting in cell cyclearrest in the S and G2/M phases to allow for repair of DNA damage(reviewed in Cancer Cell, Bartek and Lukas, Volume 3, Issue 5, May 2003,Pages 421-429. Inhibition of Chk1 has been shown to abrogate cell cyclearrest leading to enhanced tumor cell death following DNA damage by arange of chemotherapeutics. Cells lacking intact G1 checkpoints areparticularly dependent on S and G2/M checkpoints and are thereforeexpected to be more sensitive to chemotherapeutic treatment in thepresence of a chk1 inhibitor, whereas normal cells with functional G1checkpoints would be predicted to undergo less cell death.

The invention relates to 1,7-diazacarbazoles of Formula (I), (I-a),and/or (I-b) (and/or solvates, hydrates and/or salts thereof) withkinase inhibitory activity, more specifically with chk1 inhibitoryactivity. The compounds of the present invention are also useful asinhibitors of Glycogen Synthase Kinase-3 (GSK-3), KDR kinase, andFMS-like tyrosine kinase 3 (FLT3). Accordingly, the compounds of theinvention and compositions thereof are useful in the treatment ofhyperproliferative disorders such as cancer.

-   X is CR² or N;-   Y is CR⁴ or N;-   Z is CR⁸ or N; provided that no more than one of X, Y and Z is N at    the same time;-   R² is H, halo, CN, CF₃, —OCF₃, OH, —NO₂, C₁-C₅ alkyl, —O(C₁-C₅    alkyl), —S(C₁-C₅ alkyl), or N(R²²)₂;-   R³ is H, halo, CN, —O—R⁹, —N(R²²)—R⁹, —S(O)_(p)—R⁹, or R⁹;-   p is 0, 1 or 2;-   R⁴ is H, halo, CN, CF₃, —OCF₃, OH, —NO₂, —(CR¹⁴R¹⁵)_(n)C(═Y′)OR¹¹,    —(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹¹R¹²,    —(CR¹⁴R¹⁵)_(n)OR¹¹, —(CR¹⁴R¹⁵)_(n)S(O)_(p)R¹¹,    —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)OR¹¹,    —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y″)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹²SO₂R¹¹,    —(CR¹⁴R¹⁵)_(n)OC(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y′)NR¹¹R¹²,    —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹¹R¹², alkyl, alkenyl, alkynyl, cycloalkyl,    heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl,    alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are    optionally substituted with one to four R¹³ groups;-   each n is independently 0-5;-   R⁵ is H, halo, CN, CF₃, —OCF₃, OH, —NO₂, —(CR¹⁴R¹⁵)_(n)C(═Y′)OR¹¹,    —(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)R¹¹,    —(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹,    —(CR¹⁴R¹⁵)_(n)S(O)_(p)R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)OR¹¹,    —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹²SO₂R¹¹,    —(CR¹⁴R¹⁵)_(n)OC(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y′)NR¹¹R¹²,    —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹¹R¹², alkyl, alkenyl, alkynyl, cycloalkyl,    heterocyclyl, aryl, heteroaryl wherein the said alkyl, alkenyl,    alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are    optionally substituted with one to four R¹³ groups;-   R⁶ is H, CN, —CF₃, —OCF₃, halo, —C(═Y′)OR¹¹, —C(═Y′)NR¹¹R¹², —OR¹¹,    —OC(═Y′)R¹¹, —NR¹¹R¹², —NR¹²C(═Y′)R¹¹, —NR¹²C(═Y′)NR¹¹R¹²,    —NR¹²S(O)_(q)R¹¹, —SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —OC(═Y′)NR¹¹R¹²,    —S(O)₂NR¹¹R¹², alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,    aryl, or heteroaryl wherein said alkyl, alkenyl, alkynyl,    cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally    substituted by one to four R¹³ groups;-   R⁷ is H, OH, CN, O(C₁-C₃ alkyl), or C₁-C₄ alkyl, wherein each said    alkyl is optionally substituted with one to three groups    independently selected from halo, N(R²²)₂ or OR²²;-   R⁸ is H, halo, CN, NO₂, N(R²²)₂, OH, O(C₁-C₃ alkyl), or C₁-C₃ alkyl,    wherein each said alkyl is optionally substituted with one to three    fluoro groups;-   each R⁹ is independently alkyl, alkenyl, alkynyl, cycloalkyl,    heterocyclyl, aryl, heteroaryl, wherein each member of R⁹ is    independently substituted with one to three R¹⁰ groups;-   each R¹⁰ is independently H, CN, —CF₃, —OCF₃, —NO₂, halo, R¹¹,    —OR¹¹, —NR¹²C(═Y′)R¹¹, —NR¹²C(═NR¹²)R¹¹, —NR¹²S(O)_(q)R¹¹, —SR¹¹,    —NR¹¹R¹², oxo, —C(═Y′)OR¹¹, —C(═Y′)NR¹¹R¹², —S(O)_(q)R¹¹,    —NR¹²C(═Y′)OR¹¹, —NR¹²C(═Y′)NR¹¹R¹², —(═Y′)R¹¹, —OC(═Y′)NR¹¹R¹², or    —S(O)₂NR¹¹R¹²;-   each q independently is 1 or 2;-   R¹¹ and R¹² are independently H, alkyl, cycloalkyl, heterocyclyl,    aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl,    aryl and heteroaryl are optionally substituted with one to four R¹³    groups, wherein two geminal R¹³ groups are optionally taken together    with the atom to which they are attached to form a 3-6 membered ring    having additional 0-2 heteroatoms selected from O, S, and N, said    ring being optionally substituted with one to four R¹⁸ groups;-   R¹¹ and R¹² are optionally taken together with the attached N atom    to form a 4-7 membered ring having additional 0-2 heteroatoms    selected from O, S, and N, said ring being optionally substituted    with one to four R¹³ groups;-   each R¹³ is independently halo, CN, CF₃, —OCF₃, —NO₂, oxo,    —(CR¹⁴R¹⁵)_(n)C(═Y′)R¹⁶, —(CR¹⁴R¹⁵)_(n)C(═Y′)OR¹⁶,    —(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷,    —(CR¹⁴R¹⁵)_(n)OR¹⁶, —(CR¹⁴R¹⁵)_(n)SR¹⁶, —(CR¹⁴R¹⁵)_(n)NR¹⁶C(═Y′)R¹⁷,    —(CR¹⁴R¹⁵)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁴R¹⁵)_(n)NR¹⁷C(═Y′)NR¹⁶R¹⁷,    —(CR¹⁴R¹⁵)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁴R¹⁵)_(n)OC(═Y′)R¹⁶,    —(CR¹⁴R¹⁵)_(n)OC(═Y′)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)S(O)R¹⁶,    —(CR¹⁴R¹⁵)_(n)S(O)₂R(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷, or R¹⁶;-   R¹⁴ and R¹⁵ are independently selected from H, alkyl, cycloalkyl,    heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl,    heterocyclyl, aryl and heteroaryl are optionally substituted with    one to four R¹⁸ groups;-   R¹⁶ and R¹⁷ are independently H, alkyl, cycloalkyl, heterocyclyl,    aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl,    aryl and heteroaryl are optionally substituted with one to four R¹⁸    groups;-   R¹⁶ and R¹⁷ are optionally taken together with the attached N atom    to form a 5-6 membered ring having additional 0-2 heteroatoms    selected from O, S, and N, said ring being optionally substituted    with one to four R¹⁸ groups;-   each R¹⁸ is independently H, alkyl, cycloalkyl, heterocyclyl, aryl,    heteroaryl, halo, CN, CF₃, —OCF₃, —NO₂, oxo,    —(CR¹⁹R²⁰)_(n)C(′Y′)R²³, —(CR¹⁹R²⁰)_(n)C(═Y′)OR²³,    —(CR¹⁹R²⁰)_(n)C(═Y′)NR²³R²⁴, —(CR¹⁹R²⁰)_(n) NR²³R²⁴,    —(CR¹⁹R²⁰)_(n)OR²³, —(CR¹⁹R²⁰)_(n)—SR²³,    —(CR¹⁹R²⁰)_(n)NR²⁴C(═Y′)R²³, —(CR¹⁹R²⁰)_(n)NR²⁴C(═Y′)OR²³,    —(CR¹⁹R²⁰)_(n)NR²²C(═Y′)NR²³R²⁴, —(CR¹⁹R²⁰)_(n)NR²⁴SO₂R²³,    —(CR¹⁹R²⁰)_(n)OC(═Y′)R²³, —(CR¹⁹R²⁰)_(n)OC(═Y′)NR²³R²⁴,    —(CR¹⁹R²⁰)_(n)S(O)R²³, —(CR¹⁹R²⁰)_(n)S(O)₂R²³, or    —(CR¹⁹R²⁰)_(n)S(O)₂NR²³R²⁴, wherein said alkyl, cycloalkyl,    heterocyclyl, aryl, and heteroaryl are optionally substituted with    one to four R²¹ groups;-   R¹⁹ and R²⁰ are independently H, alkyl, cycloalkyl, heterocyclyl,    aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl,    aryl and heteroaryl are optionally substituted with one to four R²⁵    groups;-   R²³ and R²⁴ are independently H, alkyl, cycloalkyl, heterocyclyl,    aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl,    aryl and heteroaryl are optionally substituted with one to four R²¹    groups;-   R²³ and R²⁴ are optionally taken together with the attached N atom    to form a 5-6 membered ring having additional 0-2 heteroatoms    selected from O, S, and N, said ring being optionally substituted    with one to four R²¹ groups;-   each R²¹ is independently H, alkyl, cycloalkyl, heterocyclyl, aryl,    heteroaryl, halo, CN, CF₃, —OCF₃, —NO₂, oxo, —C(═Y′)R²⁵,    —C(═Y′)OR²⁵, —C(═Y′)NR²⁵R²⁶, —NR²⁵R²⁶, —OR²⁵, —SR²⁵, NR²⁶C(═Y′)NR²⁵,    —NR²⁶C(═Y′)OR²⁵, NR²²C(═Y′)NR²⁵R²⁶, —NR²⁶SO₂R²⁵, —OC(═Y′)R²⁵,    —OC(═Y′)NR²⁵R²⁶, —S(O)R²⁵, —S(O)₂R²⁵, or —S(O)₂NR²⁵R²⁶, wherein said    alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally    substituted with one to four R²⁵ groups;-   each R²⁵ and R²⁶ is independently H, alkyl, cycloalkyl,    heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl,    heterocyclyl, aryl, or heteroaryl is optionally substituted with one    to four groups selected from halo, —CN, —OCF₃, —CF₃, —NO₂, —C₁-C₆    alkyl, —OH, oxo, —SH, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂,    —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H,    —CO₂(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆    alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl),    —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂,    —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆    alkyl), —OC(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl),    —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆    alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆    alkyl)₂, —NHC(O)O(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆    alkyl);-   R²⁵ and R²⁶ are optionally taken together with the attached N atom    to form a 5-6 membered ring having additional 0-2 heteroatoms    selected from O, S, and N, said ring being optionally substituted    with one to four groups selected from halo, —CN, —OCF₃, CF₃, —NO₂,    —C₁-C₆ alkyl, —OH, oxo, —SH, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂,    —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H,    —CO₂(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆    alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆ alkyl),    —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂,    —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆    alkyl), —OC(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl),    —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆    alkyl)C(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆    alkyl)₂, —NHC(O)O(C₁-C₆ alkyl), and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆    alkyl);-   Y′ is independently O, NR²², or S; and-   each R²² is independently H or C₁-C₅ alkyl.

The present invention includes a composition (e.g., a pharmaceuticalcomposition) comprising a compound of Formula (I), (I-a), and/or (I-b)(and/or solvates, hydrates and/or salts thereof) and a carrier (apharmaceutically acceptable carrier). The present invention alsoincludes a composition (e.g., a pharmaceutical composition) comprising acompound of Formula (I), (I-a), and/or (I-b) (and/or solvates, hydratesand/or salts thereof) and a carrier (a pharmaceutically acceptablecarrier), further comprising a second chemotherapeutic agent. Thepresent compositions are therefore useful for inhibiting abnormal cellgrowth or treating a hyperproliferative disorder in a mammal (e.g.,human), such as cancer.

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder in a mammal (e.g.,human) such as cancer comprising administering to said mammal atherapeutically effective amount of a compound of Formula (I), (I-a),and/or (I-b) (and/or solvates, hydrates and/or salts thereof) or acomposition thereof, alone or in combination with a secondchemotherapeutic agent.

The present invention includes a method of using the present compoundsfor in vitro, in situ, and in vivo diagnosis or treatment of mammaliancells, organisms, or associated pathological conditions. Also includedare methods for making the present compounds.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms. Examples of alkyl groups include, but are not limited to, methyl(Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃),2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl,—CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl(s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl,—C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂ CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl,1-octyl, and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to twelve carbon atoms with at least one siteof unsaturation, i.e., a carbon-carbon, sp² double bond, wherein thealkenyl radical includes radicals having “cis” and “trans” orientations,or alternatively, “E” and “Z” orientations. Examples include, but arenot limited to, ethylenyl or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), andthe like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to twelve carbon atoms with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond. Examples include,but are not limited to, ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH),and the like.

The term “cycloalkyl” refers to a monovalent non-aromatic, saturated orpartially unsaturated ring having 3 to 12 carbon atoms as a monocyclicring or 6 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycleshaving 6 to 12 atoms can be arranged, for example, as a bicyclo [4,5],[5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10ring atoms can be arranged as a bicyclo [5,6] or [6,6] system, or asbridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-14 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Some aryl groups are representedin the exemplary structures as “Ar”. Aryl includes bicyclic radicalscomprising an aromatic ring fused to a saturated, partially unsaturatedring, or aromatic carbocyclic or heterocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, indenyl, indanyl,1,2-dihydronapthalene, 1,2,3,4-tetrahydronapthyl, and the like.

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double bonds within the ring)carbocyclic radical of 3 to 14 ring atoms in which at least one ringatom is a heteroatom selected from nitrogen, oxygen and sulfur, theremaining ring atoms being C, where one or more ring atoms is optionallysubstituted independently with one or more substituents described below.A heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 4 heteroatoms selected from N, O, and S) or abicycle having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6heteroatoms selected from N, O, and S), for example: a bicyclo [4,5],[5,5], [5,6], or [6,6] system or a bridged [2.1.1], [2.2.1], [2.2.2] or[3.2.2] system. Heterocycles are described in Paquette, Leo A.;“Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York,1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. “Heterocyclyl” also includesradicals where heterocycle radicals are fused with a saturated,partially unsaturated ring, or aromatic carbocyclic or heterocyclicring. Examples of heterocyclic rings include, but are not limited to,pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl,morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Spiromoieties are also included within the scope of this definition. Examplesof a heterocyclic group wherein ring atoms are substituted with oxo (═O)moieties are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.

The term “heteroaryl” refers to a monovalent aromatic radical of 5- or6-membered rings, and includes fused ring systems (at least one of whichis aromatic) of 5-16 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl.

The heterocycle or heteroaryl groups may be carbon (carbon-linked) ornitrogen (nitrogen-linked) attached where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiophene, tetrahydrothiophene, pyrrole or pyrrolidine,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, 2-oxo-1,2-dihydropyridine, or 4-oxo-1,4-dihydropyridine;position 2 of a isoindole, or isoindoline; position 4 of a morpholine;and position 9 of a carbazole, or β-carboline.

The term “halo” refers to F, Cl, Br or I. The heteroatoms present inheteroaryl or heterocyclyl include the oxidized forms such as N⁺→O⁻,S(O) and S(O)₂.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder, such as the development or spread of cancer. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, forexample, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application. “Abnormal cell growth”, asused herein, unless otherwise indicated, refers to cell growth that isindependent of normal regulatory mechanisms. This includes, for example,the abnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (3) anytumors that proliferate by receptor tyrosine kinases; (4) any tumorsthat proliferate by aberrant serine/threonine kinase activation; and (5)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. A “tumor” comprises one or more cancerouscells. Tumors include solid and liquid tumors. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,myeloma, and leukemia or lymphoid malignancies. More particular examplesof such cancers include squamous cell cancer (e.g., epithelial squamouscell cancer), lung cancer including small-cell lung cancer, non-smallcell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamouscarcinoma of the lung, cancer of the peritoneum, hepatocellular cancer,gastric or stomach cancer including gastrointestinal cancer, pancreaticcancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer,colorectal cancer, malignant brain tumors, melanoma, endometrial oruterine carcinoma, salivary gland carcinoma, kidney or renal cancer,prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, head and neck cancer, as well as acutemyelogenous leukemia (AML).

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of chemotherapeutic agents includeErlotinib (TARCEVA®, Genentech/OSI Pharm.), Bortezomib (VELCADE®,Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent(SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate(GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin(Eloxatin®, Sanofi), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®,Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib(SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®,AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); bryostatin; callystatin;CC-1065 (including its adozelesin, carzelesin and bizelesin syntheticanalogs); cryptophycins (particularly cryptophycin 1 and cryptophycin8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin;spongistatin; folic acid analogs such as denopterin, methotrexate,pteropterin, trimetrexate; purine analogs such as fludarabine,6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such asancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens suchas calusterone, dromostanolone propionate, epitiostanol, mepitiostane,testolactone; anti-adrenals such as aminoglutethimide, mitotane,trilostane; folic acid replenisher such as frolinic acid; aceglatone;aldophosphamide glycoside; aminolevulinic acid; eniluracil; bestrabucil;bisantrene; edatraxate; defofamine; demecolcine; diaziquone;elformithine; elliptinium acetate; an epothilone; etoglucid; galliumnitrate; lentinan; lonidainine; maytansinoids such as maytansine andansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine;pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid;2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS NaturalProducts, Eugene, Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium;tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine;trichothecenes (especially T-2 toxin, verracurin A, roridin A andanguidine); urethan; dacarbazine; mannomustine; mitobronitol;mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”);chloranmbucil; 6-thioguanine; mercaptopurine; ifosfamide; mitoxantrone;novantrone; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®);ibandronate; CPT-11; difluoromethylomithine (DMFO); and pharmaceuticallyacceptable salts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors; (v) lipid kinase inhibitors; (vi) antisenseoligonucleotides, particularly those which inhibit expression of genesin signaling pathways implicated in aberrant cell proliferation, suchas, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitorsuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Other examples of “chemotherapeutic agents” that can be used incombination with the present compounds include inhibitors of MEK (MAPkinase kinase), such as XL518 (Exelixis, Inc.) and AZD6244(Astrazeneca); inhibitors of Rat such as XL281 (Exelixis, Inc.), PLX4032(Plexxikon), and ISIS5132 (Isis Pharmaceuticals); inhibitors of mTor(mammalian target of rapamycin), such as rapamycin, AP23573 (AriadPharmaceuticals), temsirolimus (Wyeth Pharmaceuticals) and RAD001(Novartis); inhibitors of PI3K (phosphoinositide-3 kinase), such asSF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3Kinhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.), andGDC-0941 (Genentech); inhibitors of cMet, such as PHA665752 (Pfizer),XL-880 (Exelixis, Inc.), ARQ-197 (ArQule), and CE-355621; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

Examples of a “chemotherapeutic agent” also include a DNA damaging agentsuch as thiotepa and CYTOXAN® cyclosphosphamide; alkylating agents (forexample cis-platin; carboplatin; cyclophosphamide; nitrogen mustardssuch as chlorambucil, chlornaphazine, chlorophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; busulphan; nitrosoureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; andtemozolomide); antimetabolites (for example antifolates such asfluoropyrimidines like 5-fluorouracil (5-FU) and tegafur, raltitrexed,methotrexate, cytosine arabinoside, hydroxyurea and GEMZAR®(gemcitabine); antitumour antibiotics such as the enediyne antibiotics(e.g., calicheamicin, especially calicheamicin gammall and calicheamicinomegaIl (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); anthracyclineslike adriamycin; dynemicin, including dynemicin A; bisphosphonates, suchas clodronate; an esperamicin; as well as neocarzinostatin chromophoreand related chromoprotein enediyne antibiotic chromophores),aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis,dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, porfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, and zorubicin; antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and NAVELBINE®(vinorelbine) and taxoids like taxoids, e.g., TAXOL® (paclitaxel;Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France);topoisomerase inhibitors (for example RFS 2000, epipodophyllotoxins likeetoposide and teniposide, amsacrine, a camptothecin (including thesynthetic analog topotecan), and irinotecan and SN-38) andcytodifferentiating agents (for example retinoids such as all-transretinoic acid, 13-cis retinoic acid and fenretinide); andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

A “chemotherapeutic agent” also includes an agent that modulates theapoptotic response including inhibitors of IAP (inhibitor of apoptosisproteins) such as AEG40826 (Aegera Therapeutics); and inhibitors ofbcl-2 such as GX15-070 (Gemin X Biotechnologies), CNDO103 (Apogossypol;Coronado Biosciences), HA14-1 (ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate),AT101 (Ascenta Therapeutics), ABT-737 and ABT-263 (Abbott); andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

The term “prodrug” as used in this application refers to a precursor orderivative form of a compound of the invention that is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). The prodrugs of this invention include,but are not limited to, ester-containing prodrugs, phosphate-containingprodrugs, thiophosphate-containing prodrugs, sulfate-containingprodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs,glycosylated prodrugs, β-lactam-containing prodrugs, optionallysubstituted phenoxyacetamide-containing prodrugs, optionally substitutedphenylacetamide-containing prodrugs, 5-fluorocytosine and other5-fluorouridine prodrugs which can be converted into the more activecytotoxic free drug. Examples of cytotoxic drugs that can be derivatizedinto a prodrug form for use in this invention include, but are notlimited to, compounds of the invention and chemotherapeutic agents suchas described above.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, hydroxylation,reduction, hydrolysis, amidation, deamidation, esterification,deesterification, enzymatic cleavage, and the like, of the administeredcompound. Accordingly, the invention includes metabolites of compoundsof the invention, including compounds produced by a process comprisingcontacting a compound of this invention with a mammal for a period oftime sufficient to yield a metabolic product thereof.

A “liposome” is a small vesicle composed of various types of lipids,phospholipids and/or surfactant which is useful for delivery of a drug(such as chk inhibitors disclosed herein and, optionally, achemotherapeutic agent) to a mammal. The components of the liposome arecommonly arranged in a bilayer formation, similar to the lipidarrangement of biological membranes.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomer” refers to compounds which have identicalchemical constitution and connectivity, but different orientations oftheir atoms in space that cannot be interconverted by rotation aboutsingle bonds.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as crystallization, electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or l meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons. Forexample, any reference to a structure of 2-hydroxypyridine include itstautomer 2-oxo-1,2-dihydropyridine, also known as 2-pyridone, and viceversa. Similarly, compounds of Formula (I-a) include the tautomericform, i.e., Formula (I-c) and compounds of Formula (I-b) include thetautomeric form, i.e., Formula (I-d).

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g.,sodium and potassium) salts, alkaline earth metal (e.g., magnesium)salts, and ammonium salts. A pharmaceutically acceptable salt mayinvolve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counter ion. The counter ion may be any organicor inorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt can have multiplecounter ions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, or with an organic acid, such as aceticacid, methanesulfonic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, a pyranosidyl acid, such as glucuronic acid orgalacturonic acid, an alpha hydroxy acid, such as citric acid ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid,such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include, but are not limited to, organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

The term “protecting group” refers to a substituent that is commonlyemployed to block or protect a particular functionality while reactingother functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ),2-(trimethylsilyl)ethoxymethyl (SEM) and 9-fluorenylmethylenoxycarbonyl(Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituentof a hydroxy group that blocks or protects the hydroxy functionality.Suitable protecting groups include acetyl and t-butyldimethylsilyl. A“carboxy-protecting group” refers to a substituent of the carboxy groupthat blocks or protects the carboxy functionality. Commoncarboxy-protecting groups include phenylsulfonylethyl, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

The terms “compound of this invention,” and “compounds of the presentinvention”, “compounds of Formula (I), (I-a), or (I-b)” and “compoundsof Formula (I), (I-a), and/or (I-b)”, unless otherwise indicated,include compounds of Formula (I), (I-a), or (I-b) and stereoisomers,geometric isomers, tautomers, solvates, metabolites, salts (e.g.,pharmaceutically acceptable salts) and prodrugs thereof. Unlessotherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds of Formula (I), (I-a), or (I-b),wherein one or more hydrogen atoms are replaced deuterium or tritium, orone or more carbon atoms are replaced by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The present invention provides 1,7-diazacarbazoles of Formula (I),(I-a), and/or (I-b) (and/or solvates, hydrates and/or salts thereof) asdescribed above with kinase inhibitory activity, such as chkl, GSK-3,KDR and/or FLT3 inhibitory activities. The present compounds areparticularly useful as chk1 kinase inhibitors.

In certain embodiments of the present invention, X is CR², and all othervariables are as defined in Formula (I), (I-a), or (I-b). In certainembodiments of the present invention, R² is H, CF₃, C₁-C₅ alkyl, orO(C₁-C₅ alkyl), and all other variables are as defined in Formula (I),(I-a), or (I-b). In certain embodiments of the present invention, R² isH, CF₃, C₁-C₃ alkyl, or O(C₁-C₃ alkyl), and all other variables are asdefined in Formula (I), (I-a), or (I-b). In certain embodiments of thepresent invention, R² is H, and all other variables are as defined inFormula (I), (I-a), or (I-b).

In certain embodiments of the present invention, X is N, and all othervariables are as defined in Formula (I), (I-a), or (I-b).

In certain embodiments of the present invention, Y is CR⁴, and all othervariables are as defined in Formula (I), (I-a), or (I-b), or as definedin any one of the embodiments herein. In certain embodiments of thepresent invention, R⁴ is H, and all other variables are as defined inFormula (I), (I-a), or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, Y is N, and all othervariables are as defined in Formula (I), (I-a), or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, Z is CR⁸, and all othervariables are as defined in Formula (I), (I-a), or (I-b), or as definedin any one of the embodiments herein. In certain embodiments of thepresent invention, R⁸ is H, and all other variables are as defined inFormula (I), (I-a), or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, Z is N, and all othervariables are as defined in Formula (I), (I-a), or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R³ is H; and all othervariables are as defined in Formula (I), (I-a), or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R³ is halo, —O—R⁹,—N(R²²)—R⁹, —S(O)_(p)—R⁹, or R⁹; and all other variables are as definedin Formula (I), (I-a), or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R³ is halo, and allother variables are as defined in Formula (I), (I-a), or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R³ is Br, and all othervariables are as defined in Formula (I), (I-a), or (I-b), or as definedin any one of the embodiments herein. In In certain embodiments of thepresent invention, R³ is F or Cl, and all other variables are as definedin Formula (I), (I-a), or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R³ is CN, and all othervariables are as defined in Formula (I), (I-a), or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁹ is alkyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl and wherein each member ofR⁹ is independently substituted with one to three R¹⁰ groups; and allother variables are as defined in Formula (I), (I-a), or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁹ is C₁-C₆ alkyl,C₂-C₃ alkynyl, C₆ cycloalkyl, 5-6-membered heterocyclyl having 1 to 2nitrogen ring atoms, C₆ aryl, or 5-6 membered monocyclic or8-10-membered bicyclic heteroaryl and wherein each member of R⁹ isindependently substituted with one to two R¹⁰ groups; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁹ is C₁-C₆ alkyl,C₂-C₃ alkynyl, C₆ aryl, or 5-6 membered monocyclic or 8-10-memberedbicyclic heteroaryl having 1 to 2 ring atoms selected from N, O and S;and wherein each member of R⁹ is independently substituted with one totwo R¹⁰ groups; and all other variables are as defined in Formula (I),(I-a) or (I-b), or as defined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁹ is isopropyl,propynyl, phenyl, pyrazolyl, furanyl, thienyl, pyridyl, imidazolyl,pyrimidinyl, benzothienyl, thiazolyl, tetrahydrothienopyridinyl,tetrahydrothiazolopyridinyl, isothiazolyl, tetrahydropyridinyl,tetrahydroisoquinolinyl, triazolyl, dihydrobenzodioxinyl,dihydroindolyl, or oxazolyl, wherein each member of R⁹ is independentlysubstituted with one to two R¹⁰ groups; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R⁹ is cyclohexyl orpiperidinyl, and wherein each member of R⁹ is independently substitutedwith one to two R¹⁰ groups; and all other variables are as defined inFormula (I), (I-a) or (I-b), or as defined in any one of the embodimentsherein.

In certain embodiments of the present invention, R³ is R⁹ and R⁹ is asdefined in any one of the embodiments herein, and all other variablesare as defined in Formula (I), (I-a) or (1-b), or as defined in any oneof the embodiments herein.

In certain embodiments of the present invention, R³ is OR⁹, and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R³ is OR⁹ and R⁹ is asdefined in any one of the embodiments herein, and all other variablesare as defined in Formula (I), (I-a) or (1-b), or as defined in any oneof the embodiments herein.

In certain embodiments of the present invention, R³ is OR⁹ and R⁹ isphenyl optionally substituted with one to three R¹⁰ groups; and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R³ is OR⁹, and R⁹ isalkyl or heterocyclyl wherein said alkyl or heterocyclyl is optionallysubstituted with one to three R¹⁰ groups; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R³ is OR⁹, and R⁹ isC₁-C₂ alkyl optionally substituted with one to two R¹⁰ groups selectedfrom N(Me)₂, NHEt, N-methylpiperidinyl and OCH₃; and all other variablesare as defined in Formula (I), (I-a) or (I-b), or as defined in any oneof the embodiments herein.

In certain embodiments of the present invention, R³ is OR⁹, and R⁹ ispiperidinyl or pyrrolidinyl wherein piperidinyl or pyrrolidinyl isoptionally substituted with one to three R¹⁰ groups; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R³ is —N(R²²)—R⁹, andR⁹ is defined in any one of the embodiments herein; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R³ is —N(R²²)—R⁹, andR⁹ is alkyl optionally substituted with one to three R¹⁰ groups; and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R³ is —N(R²²)—R⁹, andR⁹ is C₁-C₂ alkyl optionally substituted with one to two R¹⁰ groupsselected from oxo, NR¹¹R¹²; and all other variables are as defined inFormula (I), (I-a) or (I-b), or as defined in any one of the embodimentsherein. In certain embodiments of the present invention, R³ is NH-ethylor NHC(O)(N-pyrrolidinyl); and all other variables are as defined inFormula (I), (I-a) or (I-b), or as defined in any one of the embodimentsherein.

In certain embodiments of the present invention, R³ is hydrogen, fluoro,chloro, bromo, cyano, trifluoromethyl, methyl, (2-propyl),(2-hydroxy-2-propyl), (2-fluoro-2-propyl), cyclopropyl, methoxy, ethoxy,difluoromethoxy, trifluoromethoxy, (2-hydroxyethyl)oxy,(2,2,2-trifluoroethyl)oxy, methylsulfonyl, or aminosulfonyl; all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R³ is R⁹ wherein R⁹ isalkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl andwherein each member of R⁹ is independently substituted with one to threeR¹⁰ groups; and all other variables are as defined in Formula (I), (I-a)or (I-b), or as defined in any one of the embodiments herein.

In certain embodiments of the present invention, R³ is R⁹ wherein R⁹ isC₁-C₆ alkyl, C₂-C₃ alkynyl, C₄-C₆ cycloalkyl, C₆ aryl, 4-6 memberedheterocyclyl or 5-6 membered monocyclic or 8-10-membered bicyclicheteroaryl having 1 to 2 ring atoms selected from N, O and S; andwherein each member of R⁹ is independently substituted with one to twoR¹⁰ groups; and all other variables are as defined in Formula (I), (I-a)or (I-b), or as defined in any one of the embodiments herein.

In certain embodiments of the present invention, R³ is R⁹ wherein R⁹ isC₁-C₆ alkyl, C₂-C₃ alkynyl, C₆ aryl, or 5-6 membered monocyclic or8-10-membered bicyclic heteroaryl having 1 to 2 ring atoms selected fromN, O and S; and wherein each member of R⁹ is independently substitutedwith one to two R¹⁰ groups; and all other variables are as defined inFormula (I), (I-a) or (I-b), or as defined in any one of the embodimentsherein.

In certain embodiments of the present invention, R³ is R⁹ wherein R⁹ isisopropyl, propynyl, phenyl, pyrazolyl, furanyl, thienyl, pyridyl,imidazolyl, pyrimidinyl, benzothienyl, thiazolyl,tetrahydrothienopyridinyl, tetrahydrothiazolopyridinyl, isothiazolyl,tetrahydropyridinyl, tetrahydroisoquinolinyl, triazolyl,dihydrobenzodioxinyl, dihydroindolyl, oxazolyl, ortetrahydrobenzothienyl, wherein each member of R⁹ is independentlysubstituted with one to two R¹⁰ groups; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R³ is R⁹ wherein R⁹ iscyclohexyl or piperidinyl, wherein each member of R⁹ is independentlysubstituted with one to two R¹⁰ groups; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R¹⁰ is H, halo, R¹¹,—OR¹¹, CN, —CF₃, —OCF₃, —NR¹²C(═O)R¹¹, —NR¹²S(O)_(q)R¹¹, —SR¹¹,—NR¹¹R¹², —C(═O)NR¹¹R¹², oxo, —S(O)_(q)R¹¹, —S(O)₂NR¹¹R¹², or—C(═O)OR¹¹, wherein R¹¹ and R¹² are optionally taken together with theattached N atom to form a 4-7 membered ring having additional 0-2heteroatoms selected from O, S, and N, said ring being optionallysubstituted with one to four R¹³ groups; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R¹⁰ is halo, R¹¹,—OR¹¹, CN, —CF₃, —OCF₃, —NR¹²C(═O)R¹¹, —NR¹²S(O)_(q)R¹¹, —SR¹¹,—NR¹¹R¹², —C(═O)NR¹¹R¹², oxo, —S(O)_(q)R¹¹, —S(O)₂NR¹¹R¹², (or—C(═O)OR¹¹, wherein R¹¹ and R¹² are optionally taken together with theattached N atom to form a 4-7 membered ring having additional 0-2heteroatoms selected from O, S, and N, said ring being optionallysubstituted with one to four R¹³ groups; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R¹⁰ is halo; CN; —CF₃;—OCF₃; —NR¹²C(O)R¹¹ wherein R¹² is H and R¹¹ is C₁-C₄ alkyl;—NR¹²S(O)₂R¹¹ wherein R¹² is H and R¹¹ is C₁-C₄ alkyl; —SR¹¹ wherein isH or C₁-C₄ alkyl; —NR¹¹R¹² wherein R¹¹ and R¹² are independently H orC₁-C₄ alkyl and R¹¹ and R¹² are optionally taken together with theattached N atom to form a 6-membered ring having additional 0-2heteroatoms selected from O, S, and N, said ring being optionallysubstituted with one R²² group; —C(═Y′)NR¹¹R¹² wherein R¹¹ and R¹² areindependently H or C₁-C₄ alkyl; oxo; —S(O)₂R¹¹ wherein R¹¹ is C₁-C₄alkyl, C₅-C₆ cycloalkyl or a 5-6 membered heterocyclyl having 1 to 2heteroatoms selected from N and O; or —S(O)₂NR¹¹R¹² wherein R¹¹ and R¹²are independently H or C₁-C₄ alkyl; and all other variables are asdefined in Formula (I), (I-a), or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R¹⁰ is F, Cl, CN, —CF₃,—OCF₃, —OH, —NHC(O)CH₃, —NHS(O)₂CH₃, —SCH₃, —NH₂, —N(Et)₂, —C(O)NH₂,—C(O)NH(p-methoxybenzyl), —C(O)N(Et)₂, oxo, —S(O)₂CH₃, —S(O)₂N(CH₃)₂,N-morpholinyl, N-piperidinyl, N-piperazinyl, or CO₂H, and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R¹⁰ is R¹¹, and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R¹⁰ is R¹¹ wherein R¹¹is alkyl or heterocyclyl, wherein said alkyl and heterocyclyl areoptionally substituted with one to four R¹³ groups, wherein two geminalR¹³ groups are optionally taken together with the atom to which they areattached to form a 3-6 membered ring having additional 0-2 heteroatomselected from O, S, and N, said ring being optionally substituted withone to four R¹⁸ groups; and all other variables are as defined inFormula (I), (I-a) or (I-b), or as defined in any one of the embodimentsherein.

In certain embodiments of the present invention, R¹⁰ is R¹¹ wherein R¹¹is C₁-C₆ alkyl, or 4-6 membered (e.g., 5-6 membered) monocyclic or8-10-membered bicyclic heterocyclyl having 1 to 2 heteroatoms selectedfrom N and O, wherein said alkyl and heterocyclyl are optionallysubstituted with one to four R¹³ groups, wherein two geminal R¹³ groupsare optionally taken together with the atom to which they are attachedto form a six-membered ring having 0-2 heteroatom selected from O, S,and N, said ring being optionally substituted with one to four R¹⁸groups; and all other variables are as defined in Formula (I), (I-a) or(I-b), or as defined in any one of the embodiments herein.

In certain embodiments of the present invention, R¹⁰ is R¹¹ wherein R¹¹is C₁-C₆ alkyl, or 4-6 membered (e.g., 5-6 membered) monocyclic or8-10-membered bicyclic heterocyclyl having 1 to 2 heteroatoms selectedfrom N and O, wherein said alkyl and heterocyclyl are optionallysubstituted with one to two R¹³ groups and wherein each R¹³ isindependently halo, CN, CF₃, —OCF₃, oxo, —(CR¹⁴R¹⁵)_(n)C(O)OR¹⁶,—(CR¹⁴R¹⁵)_(n)C(O)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)OR¹⁶,—(CR¹⁴R¹⁵)_(n)NR¹⁶C(O)R¹⁷, —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷, or R¹⁶; and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R¹⁰ is R¹¹ wherein R¹¹is C₁-C₆ alkyl, wherein alkyl is optionally substituted with one to twoR¹³ groups and wherein each R¹³ is independently halo, CN, CF₃, —OCF₃,oxo, —(CR¹⁴R¹⁵)_(n)C(O)OR¹⁶, —(CR¹⁴R¹⁵)_(n)C(O)NR¹⁶R¹⁷,—(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)OR¹⁶, —(CR¹⁴R¹⁵)_(n)NR¹⁶C(O)R¹⁷,—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷, or R¹⁶; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R¹⁰ is R¹¹ wherein R¹¹is methyl, ethyl, i-butyl, t-butyl, CH₂R²⁷ wherein R²⁷ is N(methyl)₂,OH, OCH₃, CH₂OH, piperazinyl, piperidinyl, morpholinyl, pyrrolyl,azetidinyl, C(CH₃)₂-piperidinyl, wherein piperazinyl or piperidinyl isoptionally substituted with one to two groups selected from methyl,ethyl, hydroxy or (CH₂)₂OH; and all other variables are as defined inFormula (I), (I-a) or (I-b), or as defined in any one of the embodimentsherein.

In certain embodiments of the present invention, R¹⁰ is R¹¹ wherein R¹¹is 5-6 membered monocyclic or 8-10-membered bicyclic heterocyclyl having1 to 2 heteroatoms selected from N and O, wherein said alkyl andheterocyclyl are optionally substituted with one to two R¹³ groups andwherein each R¹³ is independently halo, CN, CF₃, —OCF₃, oxo,—(CR¹⁴R¹⁵)_(n)C(O)OR¹⁶, —(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷,—(CR¹⁴R¹⁵)_(n)OR¹⁶, —(CR¹⁴R¹⁵)_(n)NR¹⁶C(O)R¹⁷,—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷, or R¹⁶; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R¹⁰ is —OR¹¹; and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R¹⁰ is —OR¹¹ whereinR¹¹ is H, alkyl or heterocyclyl, wherein said alkyl or heterocyclyl isoptionally substituted with one to four R¹³ groups and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R¹⁰ is —OR¹¹ whereinR¹¹ is H, C₁-C₄ alkyl, or 4-6 membered (e.g., 5-6 membered) monocyclicor 8-10-membered bicyclic heterocyclyl having 1 to 2 nitrogen atoms,wherein said alkyl or heterocyclyl is optionally substituted with one tofour R¹³ groups; and all other variables are as defined in Formula (I),(I-a) or (I-b), or as defined in any one of the embodiments herein.

In certain embodiments of the present invention, R¹⁰ is —OR¹¹ whereinR¹¹ is H, C₁-C₄ alkyl, or 4-6 membered (e.g., 5-6 membered) monocyclicor 8-membered bicyclic heterocyclyl having 1 to 2 nitrogen atoms,wherein said alkyl or heterocyclyl is optionally substituted with one totwo R¹³ groups, wherein each R¹³ is independently halo, CN, CF₃, —OCF₃,oxo, —(CR¹⁴R¹⁵)_(n)C(O)OR¹⁶, —(CR¹⁴R¹⁵)_(n)C(O)NR¹⁶R¹⁷,—(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)OR¹⁶, —(CR¹⁴R¹⁵)_(n)NR¹⁶C(O)R¹⁷,—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷, or R¹⁶; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein. In certain embodiments, R¹⁰ is OH or OCH₃; and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R³ is selected from:

H, F, Cl, Br, iPr or CO₂CH₃; and all other variables are as defined inFormula (I), (I-a) or (I-b), or as defined in any one of the embodimentsherein.

In certain embodiments of the present invention, R⁴ is H; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is H, halo,—(CR¹⁴R¹⁵)_(n)C(O)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹²C(O)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹, —(CR¹⁴R¹⁵)_(n)SR¹¹, alkyl,heterocyclyl or heteroaryl, wherein the said alkyl, heterocyclyl orheteroaryl is optionally substituted with one to four R¹³ groups; andall other variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is H, halo,—(CR¹⁴R¹⁵)_(n)C(O)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹²C(O)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)—OR¹¹, —(CR¹⁴R¹⁵)_(n)SR¹¹, alkyl,or heterocyclyl, wherein the said alkyl or heterocyclyl is optionallysubstituted with one to four R¹³ groups; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R⁵ is halo or C₂-C₆alkenyl; and all other variables are as defined in Formula (I), (I-a) or(I-b), or as defined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is H; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is Cl, Br or F; andall other variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is—(CR¹⁴R¹⁵)_(n)C(O)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹²C(O)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹, —(CR¹⁴R¹⁵)_(n)SR¹¹, C₁-C₆alkyl, or 4-6 membered (e.g., 5-6 membered) monocyclic or 7-10 memberedbicyclic heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkylor heterocyclyl is optionally substituted with one to two R¹³ groups;wherein R¹⁴ and R¹⁵ are H; n is 0-2; each R¹¹ is independently H, C₁-C₄alkyl or 5-6 membered monocyclic heterocyclyl having 1 to 2 nitrogenatoms, wherein said alkyl or heterocyclyl is optionally substituted withone to two R¹³ groups; and all other variables are as defined in Formula(I), (I-a) or (I-b), or as defined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is—(CR¹⁴R¹⁵)_(n)C(O)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹²C(O)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹, —(CR¹⁴R¹⁵)_(n)SR¹¹, C₁-C₆alkyl, or 4-6 membered (e.g., 5-6 membered) monocyclic or 7-10 memberedbicyclic heterocyclyl having 1 to 2 nitrogen atoms, wherein said alkylor heterocyclyl is optionally substituted with one to two R¹³ groups;wherein R¹⁴ and R¹⁵ are H; n is 0-2; each R¹¹ is independently H, C₁-C₄alkyl, or 5-6 membered monocyclic heterocyclyl having 1 to 2 nitrogenatoms, wherein said alkyl or heterocyclyl is optionally substituted withone to two R¹³ groups; R¹³ is OH, O(C₁-C₃ alkyl), or C₁-C₃ alkyl; andall other variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is—(CR¹⁴R¹⁵)_(n)OR¹¹, C₁-C₆ alkyl, C₂-C₆ alkenyl, or halo; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is —OR¹¹; and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is —NR¹¹; and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is C₁-C₆ alkyl, or4-6 membered (e.g., 5-6 membered) monocyclic or 7-10 membered bicyclicheterocyclyl having 1 to 2 nitrogen atoms wherein the point ofattachment is via a carbon atom on said heterocyclyl, wherein said alkylor heterocyclyl is optionally substituted with one to two R¹³ groups;and all other variables are as defined in Formula (I), (I-a) or (I-b),or as defined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is 5-6 memberedheteroaryl; and all other variables are as defined in Formula (I), (I-a)or (I-b), or as defined in any one of the embodiments herein. In certainembodiments, R⁵ is imidazolyl; and all other variables are as defined inFormula (I), (I-a) or (I-b), or as defined in any one of the embodimentsherein.

In certain embodiments of the present invention, R⁵ is F, ethyl, OH,OEt, O(CH₂)₂OH, O(pyrrolidinyl), Br, —CH═CH₂, or O(CH₂)₂OCH₃, and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁵ is tropinyl,quinuclideinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, orazetidine wherein said tropinyl, quinuclideinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, or azetidine is optionallysubstituted with one or more F; and all other variables are as definedin Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R⁵ is selected from thefollowing; and all other variables are as defined in Formula (I), (I-a)or (I-b), or as defined in any one of the embodiments herein: ethyl, OH,ethoxy, O(CH₂CH₂)OCH₃,

In certain embodiments of the present invention, R⁶ is H; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁶ is CN, —CF₃, —OCF₃,halo, —C(═Y′)OR¹¹, —C(═Y′)NR¹¹R¹², —OR¹¹, —OC(═Y′)R¹¹, —NR¹¹R¹²,—NR¹²C(═Y′)R¹¹, —NR¹²C(═Y′)NR¹¹R¹², —NR¹²S(O)_(q)R¹¹, —SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, —OC(═Y′)NR¹¹R¹², —S(O)₂NR¹¹R¹², alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl areoptionally substituted by one to four R¹³ groups; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁶ is CN, CF₃, —OCF₃,halo, —C(O)OR¹¹, —C(O)NR¹¹R¹², —OR¹¹, —NR¹¹R¹², —NR¹²C(O)R¹¹,—NR¹²C(═NR¹²)R¹¹, —NR¹²S(O)₂R¹¹, —SR¹¹, —S(O)₂R¹¹, alkyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl wherein said alkyl is substituted withone to four R¹³ groups except H and said heterocyclyl or heteroaryl isoptionally substituted by one to four R¹³ groups; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁶ is CN, halo,—C(O)NR¹¹R¹², —OR¹¹, —NR¹¹R¹², —NR¹²C(O)R¹¹, alkyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein said alkyl is substitutedwith one to two R¹³ groups except H, and said heteroaryl is optionallysubstituted by one to two R¹³ groups; and all other variables are asdefined in Formula (I), (I-a) or (I-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R⁶ is CN, halo,—C(O)NR¹¹R¹², —OR¹¹, —NR¹¹R¹², —NR¹²C(O)R¹¹, C₁-C₃ alkyl, C₃-C₆cycloalkyl, 5-6 heterocyclyl having 1 to 2 heteroatoms, C₆ aryl, or 5-6or 9-membered heteroaryl having 1 to 4 heteroatoms; wherein said alkylis substituted with one to two R¹³ groups except H; and said cycloalkyl,aryl, heterocyclyl or heteroaryl is optionally substituted by one to twoR¹³ groups; wherein heteroatoms are selected from N, O and S; whereineach R¹² is H or C₁-C₃ alkyl and each R¹¹ is independently H or C₁-C₃alkyl optionally substituted by one to two R¹³ groups; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁶ is CN, halo,—C(O)NR¹¹R¹², —OR¹¹, —NR¹¹R¹², —NR¹²C(O)R¹¹, C₁-C₃ alkyl, or 5-6 or9-membered heteroaryl having 1 to 4 heteroatoms selected from N, O andS, wherein said alkyl is substituted with one to two R¹³ groups (whereinR¹³ is OR¹⁶ where R¹⁶ is H or alkyl), and said heteroaryl is optionallysubstituted by one to two R¹³ groups (wherein R¹³ is OR¹⁶, NR¹⁶R¹⁷, orC₁-C₂ alkyl optionally substituted with R¹⁸ where each of R¹⁶ and R¹⁷ isindependently H or alkyl); wherein each R¹² is H or C₁-C₃ alkyl and eachR¹¹ is independently H or C₁-C₃ alkyl optionally substituted by one totwo R¹³ groups (wherein R¹³ is OR¹⁶ where R¹⁶ is H or alkyl); and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁶ is CN, F, Cl, Br,—C(O)OH, —C(O)NH₂, —C(O)NHCH₂CH₂OH, —C(O)N(CH₃)₂, —OCH₃, —CH₂OH,—C(CH₃)₂OH, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, isoxazolyl,thiazolyl, imidazolyl, pyrazinyl, imidazopyrimidinyl, pyridazinyl,triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, —C(O)—N-pyrrolidinyl,—C(O)NHEt, or —C(O)NH(CH₂)₂NH₂, wherein said pyridyl, pyrazolyl,pyrimidinyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazinyl,imidazopyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, thiadiazolyl,and oxadiazolyl are optionally substituted with 1-2 groups selected frommethyl, methoxy, NH₂, and benzyl; and all other variables are as definedin Formula (I), (I-a) or (1-b), or as defined in any one of theembodiments herein.

In certain embodiments of the present invention, R⁶ is CN; and all othervariables are as defined in Formula (I), (I-a) or (I-b), or as definedin any one of the embodiments herein.

In certain embodiments of the present invention, R⁶ is pyridyl, orpyrazolyl optionally substituted with methyl; and all other variablesare as defined in Formula (I), (I-a) or (1-b), or as defined in any oneof the embodiments herein.

In certain embodiments of the present invention, R⁷ is H, or C₁-C₄ alkyloptionally substituted with one to three halo groups or OH; and allother variables are as defined in Formula (I), (I-a) or (I-b), or asdefined in any one of the embodiments herein.

In certain embodiments of the present invention, R⁷ is H, methyl orethyl; and all other variables are as defined in Formula (I), (I-a) or(I-b), or as defined in any one of the embodiments herein.

In certain embodiments, R¹⁰ is methyl, ethyl or R³⁰ as defined inFormula (II) below.

In certain embodiments, compounds are of Formula (H):

wherein R⁶ is CN,

and R³⁰ is

In certain embodiments, compounds are of Formula (H), wherein R⁶ is

wherein R¹³ is OCH₃, O-piperidinyl, O-(1-ethyl)piperidinyl orO(CH₂)₂N(CH3)₂.

In certain embodiments, compounds are of Formula (II), wherein R³⁰ is

wherein

is

In certain embodiments, compounds are of Formula (III):

wherein R⁴⁰ is

Another embodiment of the present invention includes title compoundsdescribed herein Examples 1-403 and compounds below.

wherein each R³ is independently H, hydrogen, fluoro, chloro, bromo,cyano, trifluoromethyl, methyl, (2-propyl), (2-hydroxy-2-propyl),(2-fluoro-2-propyl), cyclopropyl, methoxy, ethoxy, difluoromethoxy,trifluoromethoxy, (2-hydroxyethyl)oxy, (2,2,2-trifluoroethyl)oxy,methylsulfonyl, or aminosulfonyl.

The present compounds are prepared according to the procedures describedbelow in the schemes and examples, or by methods known in the art. Thestarting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available compounds, orprepared using well known synthetic methods. Accordingly, methods formaking the present compounds of Formula (I), (I-a) or (I-b) according toScheme 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11a, 11b, 11c, 11d, 11c, 11d, 11e,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and/or 27(27-1, 27-2, and 27-3) are within the scope of the present invention.

For example, 9H-dipyrido[2,3-b;4′,3′-d]pyrrole (also referred to asdiazacarbazole herein) compounds of formula (1-4) may be prepared usingthe synthetic route outlined in Scheme 1.

Compounds of formula (1-1) may be prepared using published methodsdescribed in the literature. Intermediates of formula (1-1) may then bebrominated in the presence of a suitable brominating agent, such asbromine, in a suitable solvent such as acetic acid, at a temperaturebetween 20° C. and 120° C., to obtain compounds of formula (1-2).

Compounds of formula (1-3) can be obtained by reaction of intermediate(1-2) with an appropriate source of ammonia, such as ammonia gas, in asuitable solvent such as methanol, at a temperature between 20° C. and65° C.

Intermediates of formula (1-3) may then be dehydrated in the presence ofa suitable dehydrating agent, such as trifluoroacetic anhydride, in asuitable solvent such as THF, at a temperature from 20° C. to theboiling point of the solvent, to obtain compounds of formula (1-4).

Compounds of formula (2-4) may also be prepared according to theprocedure shown in Scheme 2 (wherein R^(3′) is R³ or intermediatemoieties that may be manipulated to give R³, and R^(6′) is R⁶ orintermediate moieties that may be manipulated to give R⁶). The boronicacid of formula (2-2, where R═H) may be prepared from compounds offormula (2-1) by treatment with a base such as butyllithium in thepresence of an alkyl borate such as trimethyl borate in a suitablesolvent such as THF at a temperature between −78° C. and ambienttemperature.

Alternatively, the boronate ester of formula (2-2, where R=alkyl) may beprepared from compounds of formula (2-1) with the appropriatealkylatodiboron in the presence of a catalyst such asbis(diphenylphosphino)ferrocene palladium(II) dichloride, using asuitable base such as potassium acetate in a solvent such as dioxane ata temperature from room temperature to the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C.

Compounds of formula (2-4) may be prepared according to the procedureshown in Scheme 2 by reaction of compounds of formula (2-2) withappropriate halide of formula (2-3) (incorporating appropriatesubstituents R^(3′)), in the presence of a catalyst such asbis(triphenylphosphine) palladium(II)dichloride, with a base such asaqueous sodium carbonate in a suitable co-solvent such as acetonitrileat a temperature from room temperature to the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C.

The protecting group (P₁) of compounds of formula (2-1), (2-2) and (2-4)may be manipulated at any stage of the synthesis. A protecting groupsuch as SEM (trimethylsilyl ethoxymethyl), can be installed using analkylating agent such as SEM-chloride, in a solvent such as DMF in thepresence of a suitable base such as sodium hydride. Compounds of generalformula (2-4) where P₁ is a protecting group such as SEM may bede-protected using a reagent such as tetrabutylammonium fluoride in asolvent such as THF at a temperature between −20° C. and 50° C. toprovide compounds where P₁ is H.

Compounds of general formula (3-4) may also be prepared according to theprocedure shown in Scheme 3 (wherein R^(3′) is R³ or intermediatemoieties that may be manipulated to give R³, and R^(6′) is R⁶ orintermediate moieties that may be manipulated to give R⁶). Stannanes ofgeneral formula (3-2) may be prepared from compounds of formula (3-1)with a base and the appropriate tin halide in a suitable solvent such asTHF.

Alternatively, stannanes of general formula (3-2) may be prepared fromcompounds of formula (3-1) with the appropriate alkylditin (containingsuitable R groups) in the presence of a catalyst such astetrakis(triphenylphosphine) palladium(0) in a suitable solvent such astoluene at a temperature from room temperature to the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 150° C.

Compounds of general formula (3-4) may be prepared from compounds ofgeneral formula (3-2) with the appropriate halide or triflate of formula(3-3), in the presence of a catalyst such astetrakis(triphenylphosphine) palladium(0) in a suitable solvent such asdioxane at a temperature from room temperature to the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 150° C.

Compounds of general formula (4-6) may be obtained from commercialsources or prepared using published methods described in the literature.Compounds of general formula (4-6) may also be prepared according to theprocedure shown in Scheme 4.

Compounds of general formula (4-3) may be obtained from compounds offormula (4-1) by reaction with a halogenated pyridine or triflate offormula (4-2) in the presence of a transition metal catalyst such asbis(triphenylphosphine) palladium(II) dichloride, a base such as aqueoussodium carbonate in a suitable solvent such as acetonitrile at atemperature from room temperature to the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C.

The 2-cyanopyridines of formula (4-4) may be prepared from2-halopyridines of formula (4-3) by reaction with an inorganic cyanidesuch as zinc cyanide, in the presence of a transition metal catalystsuch as tetrakis(triphenylphosphine) palladium(0), in a solvent such asDMF, at a temperature from 50° C. to reflux temperature of the solvent,or under microwave irradiation at a temperature between 70° C. and 200°C. The aminopyridine (4-4) may then be halogenated with a halogenatingagent such as N-bromosuccinimide in a solvent such as DMF at atemperature between room temperature and 50° C. to give intermediates offormula (4-5).

Cyclisation of compounds with general formula (4-5) with a suitable basesuch as sodium hexamethyldisilazide in a suitable solvent such as THF ata temperature between 0° C. and 50° C. may give compounds of generalformula (4-6).

Compounds of general formulae (5-2), (5-3) and (5-4) may be preparedusing published methods described in the literature. Compounds offormulae (5-2), (5-3) and (5-4) may also be prepared using the syntheticroutes outlined in Scheme 5 (wherein R^(3′) is R³ or intermediatemoieties that may be manipulated to give R³).

Compounds of general formula (5-2) may be obtained from compounds offormula (5-1) by reaction with a reagent such as n-butyllithium in apolar aprotic solvent such as THF or diethylether at temperaturesbetween −100° C. and 0° C. and quenched with a boronic ester such astrimethyl borate or triisopropyl borate.

Compounds of general formula (5-3) may be obtained from compounds offormula (5-1) by reaction with a reagent such as bis(pinacolato)diboranein the presence of a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in thepresence of a base such as potassium acetate in a suitable solvent suchas dioxane, or a mixture of two or more appropriate solvents, at atemperature between room temperature to the reflux temperature of thesolvent or solvents, or under microwave irradiation at a temperaturebetween 70° C. and 160° C.

Compounds of general formula (5-4) may be obtained from compounds offormula (5-1) by reaction with a reagent such as hexamethylditin ortriethyltin chloride in the presence of a catalyst such astetrakis(triphenylphosphine)palladium (0), in the presence of a basesuch as potassium carbonate in a suitable solvent such as DMF, or amixture of two or more appropriate solvents, at a temperature betweenroom temperature to the reflux temperature of the solvent or solvents,or under microwave irradiation at a temperature between 70° C. and 160°C.

Alternatively, these compounds of general formula (5-4) may be obtainedfrom compounds of formula (5-1) by reaction with a reagent such asn-butyllithium in a suitable aprotic solvent such as THF at temperaturesbetween −100° C. and 25° C. and then reacted with a reagent such ashexamethylditin or triethyltin chloride in a suitable aprotic solventsuch as THF at temperatures between −100° C. and 50° C.

Compounds of general formula (6-3) may be prepared using publishedmethods described in the literature. Compounds of formula (6-3) may alsobe prepared using the synthetic routes outlined in Scheme 6 (whereinR^(3′) is R³ or intermediate moieties that may be manipulated to giveR³, and R^(6′) is R⁶ or intermediate moieties that may be manipulated togive R⁶). Compounds of general formula (6-3) may be obtained fromcompounds of formula (6-1) by reaction with a boronic acid or boronateester of formula (6-2) (incorporating appropriate substituents R^(3′)),or by reaction with an aryl or alkyl tin compound of formula (6-4)(incorporating appropriate substituents R^(3′)), in the presence of acatalyst such as bis(triphenylphosphine)palladium(II)dichloride,[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II), anaqueous base such as sodium carbonate, in a suitable solvent such asacetonitrile or combination of solvents, at a temperature between roomtemperature to the reflux temperature of the solvent, or under microwaveirradiation at a temperature between 70° C. and 150° C.

Compounds of general formula (7-8) may be prepared using publishedmethods described in the literature. Compounds of formula (7-8) may alsobe prepared using the synthetic routes outlined in Scheme 7 (whereinR^(6′) is R⁶ or intermediate moieties that may be manipulated to giveR⁶). Compounds of general formula (7-3) may be obtained from compoundsof general formula (7-1) and a suitable alkyne (7-2) (incorporating agroup R¹⁰ that could be either maintained without modification aftercoupling, or that could later be modified to give other groups)R¹⁰ byreaction in the presence of a catalyst system such astetrakis(triphenylphosphine) palladium(0) and copper (I) iodide in thepresence of a base such as triethylamine and a suitable solvent such asN,N-dimethylformamide at a temperature between room temperature and theboiling point of the solvent. Such a coupling reaction could also becarried out in the presence of palladium on carbon, triphenylphosphine,copper (I) iodide and triethylamine in the presence of a suitablesolvent such as acetonitrile at a temperature between room temperatureand the reflux temperature of the solvent or solvents, or undermicrowave irradiation at a temperature between 70° C. and 160° C.

Compounds of general formula (7-6) may be obtained from compounds ofgeneral formula (7-3) and hydrogen in the presence of a suitablecatalyst such as Lindlar catalyst or palladium on barium sulfate in thepresence of quinoline and a suitable solvent such as methanol orethanol. Compounds of general formula (7-6) may also be obtained byreaction of a compound of general formula (7-1) with a suitable alkene(7-4) (incorporating a group R¹⁰ that could be either maintained withoutmodification after coupling or that could later be modified to giveother groups R¹⁰) in the presence of a base such as triethylamine orpotassium carbonate, a phosphine such as triphenyl phosphine, a metalspecies such as palladium acetate and a solvent such as acetonitrile ata temperature between room temperature and the boiling point of thesolvent. Compounds of general formula (7-6) may also be obtained by thereaction of a compound of general formula (7-1) by reaction with a vinylstannane (7-5) (incorporating a group R¹⁰ that could be eithermaintained without modification after coupling or that could later bemodified to give other groups)R¹⁰ in the presence of a metal speciessuch as tetrakis(triphenylphosphine)palladium (0) in a suitable solventsuch as toluene.

Compounds of general formula (7-8) may be obtained from compounds ofgeneral formula (7-3) or (7-6) by reaction with hydrogen in the presenceof a catalyst such as palladium on carbon or platinum oxide monohydratein a suitable solvent such as methanol or ethanol.

Compounds of general formula (7-8) may also be obtained by reaction ofcompounds of general formula (7-1) by reaction with a suitable alkylzinc reagent (7-7) in the presence of a catalyst such as allyl palladium(II) chloride dimer or bis(tri-tert-butylphosphine)palladium (0) and asuitable solvent such as 1,4-dioxane at a temperature between roomtemperature and the boiling point of the solvent.

Compounds of general formula (8-3) may be prepared from compounds ofgeneral formula (8-1) by reaction with a suitable 1,3-dipole such astrimethylsilylazide in a suitable solvent such as toluene at atemperature between room temperature and the boiling point of thesolvent.

Compounds of general formula (8-2) may be obtained from compounds ofgeneral formula (8-1) and hydrogen in the presence of a suitablecatalyst such as Lindlar catalyst or palladium on barium sulfate in thepresence of quinoline and a suitable solvent such as methanol orethanol.

Compounds of general formula (8-3) may be obtained by reaction ofcompounds of general formula (8-2) with a suitable 1,3-dipole (or itsprecursors, incorporating a group R¹⁰ that could be either maintainedwithout modification after coupling or that could later be modified togive other R¹⁰ groups) such as N-methoxymethyl-N-(trimethylsilylmethyl)benzylamine and lithium fluoride in a solvent such as acetonitrile withultrasonic treatment, or nitroethane and phenyl isocyanate in a suitablesolvent such as toluene in the presence of a base such as triethylamineat a temperature between 0° C. and the boiling point of the solvent.

Compounds of general formula (9-2) may be prepared using publishedmethods described in the literature. Compounds of formula (9-2) may beprepared using the synthetic routes outlined in Scheme 9 (wherein R^(9′)is R⁹ or intermediate moieties that may be manipulated to give R⁹, andR^(6′) is R⁶ or intermediate moieties that may be manipulated to giveR⁶).

Compounds of general formula (9-2) may be obtained from compounds offormula (9-1) by reaction with compounds of general formula (HY′—R⁹′) inthe presence of reagents such as copper(II) iodide or copper powder inthe presence of a base such as cesium carbonate in a suitable solventsuch as DMF at a temperature between room temperature and the refluxtemperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 240° C., which may be similar toconditions described in the literature by Ullmann.

Compounds of general formula (9-2) may be obtained from compounds offormula (9-1) by reaction with compounds of general formula (HY′-R⁹′) inthe presence of a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in thepresence of a base such as potassium tert-butoxide in a suitable solventsuch as DME, or a mixture of two or more appropriate solvents, at atemperature between room temperature and the reflux temperature of thesolvent or solvents, or under microwave irradiation at a temperaturebetween 70° C. and 160° C., which may be similar to conditions describedin the literature by Buchwald and Hartwig.

Compounds of general formula (10-7), (10-8) and (10-9) may be preparedusing published methods described in the literature (WO2006001754).Compounds of formula (10-7), (10-8) and (10-9) may be prepared using thesynthetic routes outlined in Scheme 10 (wherein R^(3′) is R³ orintermediate moieties that may be manipulated to give R³, and R^(5′) isR⁵ or intermediate moieties that may be manipulated to give R⁵).Compounds with a general formula (10-2) may be prepared from compoundsof formula (10-1) by deprotonation using a suitable base such as lithiumdiisopropylamide in a suitable solvent such as THF at a temperaturebetween −78° C. and room temperature followed by addition of a suitablemethylating agent such as methyl iodide. The intermediate (10-2) maythen be brominated with a brominating agent such as N-bromosuccinimidein a solvent such as carbon tetrachloride at a temperature between roomtemperature and the reflux temperature of the solvent to give compoundsof formula (10-3).

Compounds of formula (10-3) may be converted to compounds of formula(10-4) by displacement with tosylaminoacetonitrile using a suitable basesuch as sodium hydride in a solvent such as DMF at a temperature between−20° C. and 50° C. Intermediates (10-4) may then be cyclised with asuitable base such as lithium hexamethylsilylamide in a solvent such asTHF at a temperature between −20° C. and 50° C. to provide compounds ofgeneral formula (10-5). The phenol (10-5) may then be reacted with anappropriate alcohol (R^(11′)OH) using a phosphine and a coupling reagentsuch as diisopropylazodicarboxylate in an appropriate solvent such asTHF to provide ethers of general formula (10-7).

Alternatively, the phenol intermediate (10-5) may be converted to thetriflate using a reagent such as triflic anhydride in the presence of abase such as triethylamine in a suitable solvent such as dichloromethaneat a temperature between −50° C. and 20° C. The triflate (10-6) may thenbe converted to compounds of general formula (10-9) by reaction with aboronic acid or boronate ester of formula (10-10) in the presence of atransition metal catalyst such as bis(triphenylphosphine)palladium(II)dichloride, a base such as aqueous sodium carbonate in asuitable solvent such as acetonitrile at a temperature from roomtemperature to the reflux temperature of the solvent, or under microwaveirradiation at a temperature between 70° C. and 150° C. Alternatively,the triflate may be converted to compounds of general formula (10-8) bydisplacement with a suitable amine either (HNR^(11′)R^(12′)) as solventor in a solvent such as 2-propanol at a temperature between ambienttemperature and the reflux point of the solvent.

Compounds of general formula (10-8) may be obtained from compounds offormula (10-6) by reaction with compounds of general formula(HNR^(11′)R^(12′)) in the presence of a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in thepresence of a base such as potassium tert-butoxide in a suitable solventsuch as DME, or a mixture of two or more appropriate solvents, at atemperature from room temperature to the reflux temperature of thesolvent or solvents, or under microwave irradiation at a temperaturebetween 70° C. and 160° C., which may be similar to conditions describedin the literature by Buchwald and Hartwig.

Compounds of general formula (11-6) may be prepared using publishedmethods described in the literature. Compounds of formula (11-6) may beprepared using the synthetic routes outlined in Scheme 11a (whereinR^(3′) is R³ or intermediate moieties that may be manipulated to giveR³, and wherein R^(6′) is R⁶ or intermediate moieties that may bemanipulated to give R⁶). Compounds of the formula (11-1) may beconverted via acyl hydrazide formation, diazotization and Curtiusrearrangement to give compounds of the formula (11-4), which maybefurther converted by Sandmeyer reaction to compounds of the formula(11-5). Similarly, compounds of formula (11-4) may undergo Sandmeyerreaction to provide other 6-substituted derivatives such as 6-fluoro(11-7), 6-chloro (11-8), 6-iodo (11-9), 6-alkylthio (11-10), 6-hydroxy(11-11) and 6-cyano (11-12) as outlined in Scheme 11b.

Compounds of the formula (11-5) are useful for the introduction of groupR⁶ (or group R^(6′) which may be converted into group R⁶) in variousways, to generate compounds of the formula (11-6), for example, bycoupling with organic boronic acid derivatives in the presence of apalladium catalyst. Similarly, organic stannanes (eg. R^(6′)SnR₃),organozinc (R^(6′)ZnCl) and other reagents can be used in the place oforganic boronic acids. In particular compounds of the formula (11-6)where R^(6′) represents such groups as alkyl, cycloalkyl, alkenyl,alkynyl, aryl, heterocyclyl and heteroaryl may be prepared in thismanner. Compounds of the formula (11-5) may also be converted intoorganic boronic acid derivatives of the type (11-13), which may givecompounds of the formula (11-6) by coupling with organic halide ortriflate derivatives in the presence of a palladium catalyst, asoutlined in Scheme 11c. Similarly (11-5) may be converted to an organicstannane, organozinc and other derivatives to be used in the place oforganic boronic acids in palladium catalyst-mediated couplings to givecompounds of the formula (11-6).

Compounds of general formula (11-5) are useful in the preparation ofderivatives through nucleophilic aromatic displacement reactionsutilizing nucleophilic reagents R-NuH, which may be facilitated in thepresence of base, as outlined in Scheme 11d. Examples of such reagentsand reactions are alcohols yielding compounds of the formula (11-14),thiols yielding compounds of the formula (11-15), primary and secondaryamines yielding compounds of the formula (11-16), and heterocycles suchas imidazole which yields compounds of the formula (11-17). Suchdisplacement reactions may also be facilitated by the presence of apalladium, copper or other catalyst yielding compounds of the generalformula (11-18), as outlined in Scheme 11d.

Compounds of general formula (11-5) are useful in the preparation ofderivatives through nucleophilic aromatic displacement reactionsutilizing nucleophilic reagents R-NuH, which may be facilitated in thepresence of base, as outlined in. Scheme 11d. Examples of such reagentsand reactions are alcohols yielding compounds of the formula (11-14),thiols yielding compounds of the formula (11-15), primary and secondaryamines yielding compounds of the formula (11-16), and heterocycles suchas imidazole which yields compounds of the formula (11-17). Suchdisplacement reactions may also be facilitated by the presence of apalladium, copper or other catalyst yielding compounds of the generalformula (11-18), for example reactions of alcohols and alkyl amines, asoutlined in Scheme 11d.

Compounds of the formula (11-1) are also of use as intermediates for thepreparation of benzylic alcohols through nucleophilic addition oforganometallic or hydride transfer reagents to the ester function, forexample methylmagnesium bromide, to provide tertiary alcohols of theformula (11-19), as outlined in Scheme 11e. Compounds of the formula(11-1) may also be subject to partial reduction of the ester function toyield aldehydes of the formula (11-20), for example using hydridetransfer reagents such as diisobutylaluminium hydride. Suchintermediates as (11-20) may be transformed through nucleophilicaddition of organometallic reagents to the aldehyde function, forexample ethylmagnesium bromide, to provide secondary alcohols of theformula (11-21). Such benzylic alcohols may further be transformed byO-alkylation, for example utilizing alkyl halide and base, such astransformation of compounds of the formula (11-21) to ether products ofthe formula (11-22). Aldheydes of the formula (11-20) may also besubject to reductive amination utilizing amines and hydride transferreagents, for example sodium cyanoborohydride, yielding benzylic aminesof the general formula (11-22), as outlined in Scheme 11e.

Reagents and conditions given in Schemes 11a, 11b, 11c, 11d and 11e areexamples of those that may be used, and comparable methods utilizingalternative reagents can be found in the literature.

Compounds of general formula (12-1) may be prepared using methodsdescribed herein, and compounds of formula (12-6) may be prepared usingthe synthetic routes outlined in Scheme 12 (wherein R^(3′) is R³ orintermediate moieties that may be manipulated to give R³, and wherein Eis a generalized functional group derived from reaction with anelectrophilic reagent following suitable work-up procedure, and P is asuitable protecting group). Carboxylic ester compounds of the formula(12-1) may be saponified to generate compounds of the formula (12-2),for example using aqueous lithium hydroxide. Alternatively, compounds ofthe formula (12-1) may be transformed into carboxamide compounds of theformula (12-4), by treatment for example with neat tert-butylamine.Compounds such as (12-2) may be treated two or more equivalents of withstrong base, for example lithium tetramethylpiperidide, and quenchedwith a variety of electrophilic reagents, to generate derivatives of thegeneral formula (12-3), in which the 5-position has become substitutedwith a functionality E derived form the electrophilic reagent. Such atransformation is exemplified by in the literature (WO 2003022849). Forexample, suitable electophilic reagents yielding derivatives withfunctional groups E include, respectively: ethyl iodide yielding5-ethyl; formaldehyde yielding 5-hydroymethyl; dimethylformamideyielding 5-formyl; trimethylborate yielding 5-boronic acid ester, whichmay be further transformed to 5-hydroxy through oxidation using basichydrogen peroxide. Similarly, carboxamide compounds of the formula(12-4) yield products of the formula (12-5) upon similar treatment, andthese products may be further converted to the 6-cyano derivatives offormula (12-6) by treatment with acidic dehydrating agents, for examplephosphorous oxychloride.

Reagents and conditions given in Scheme 12 are examples of those thatmay be used, and comparable methods utilizing alternative reagents canbe found in the literature.

In a similar manner to that outlined in Scheme 14, compounds of thegeneral formula (13-4) may be prepared using the synthetic routesoutlined in Scheme 13 (wherein R^(3′) is R³ or intermediate moietiesthat may be manipulated to give R³, R^(5′) is R⁵ or intermediatemoieties that may be manipulated to give R⁵, R^(6′) is R⁶ orintermediate moieties that may be manipulated to give R⁶, and R^(8′) isR⁸ or intermediate moieties that may be manipulated to give R⁸). Forexample, iodo-amino-heterocycle compounds of the formula (13-4) may becoupled with heterocycle-boronic acids of the formula (13-2) utilizing asuitable palladium catalyst and base, for exampledichlorobis(triphenylphosphine)palladium(0) and potassium acetate in asuitable solvent, to yield biaryl compounds of the formula (13-3). Suchcompounds may be further transformed through treatment with base, forexample sodium hexamethyldisilazide in a suitable solvent, to yieldtricyclic compounds of the general formula (13-4). Thus furthersubstitution of the tricycle, for example at the 3-, 5-, 6-, and8-positions, may be achieved through utilizing compounds of the formula(13-1) and (13-2) in which one or more functionality R³′, R^(5′), R^(6′)or R^(8′) is already in place.

Compounds of formula (14-7) and (14-9) may be prepared using thesynthetic routes outlined in Scheme 14.

Compounds of general formula (14-3) may be obtained from compounds offormula (14-1) by reaction with a boronic acid or boronate ester offormula (14-2), in the presence of a catalyst such asbis(triphenylphosphine)palladium(II) dichloride, a base such as aqueoussodium carbonate in a suitable solvent such as acetonitrile at atemperature between room temperature and the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C. Compounds of general formula (14-3) may be cyclised toobtain compounds of formula (14-4) with a suitable base such as sodiumhexamethyldisilazane in a suitable solvent such as THF at a temperaturebetween 0° C. and 50° C.

Compounds of general formula (14-4) may then be converted to compoundsof general formula (14-6) by reaction with a boronic acid or boronateester (incorporating appropriate substituents R^(6′)), in the presenceof a catalyst such as bis(triphenylphosphine) palladium(II) dichloride,a base such as aqueous sodium carbonate in a suitable solvent such asacetonitrile at a temperature between room temperature and the refluxtemperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 150° C. Alternatively, Compounds offormula (14-4) may be coupled with an aryl or alkyl tin compound(incorporating appropriate substituents R^(6′)), in the presence of acatalyst such as bis(triphenylphosphine) palladium(II) dichloride or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), with orwithout an aqueous base such as sodium carbonate, in a suitable solventsuch as acetonitrile at a temperature between room temperature and thereflux temperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 150° C.

Compounds of general formula (14-6) may be obtained from compounds offormula (14-4) by reaction with compounds of general formula (HX—R₆′) inthe presence of a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), in thepresence of a base such as potassium tert-butoxide in a suitable solventsuch as DME, or a mixture of two or more appropriate solvents, at atemperature between room temperature and the reflux temperature of thesolvent or solvents, or under microwave irradiation at a temperaturebetween 70° C. to 160° C., as which may be similar to conditionsdescribed in the literature by Buchwald and Hartwig.

Intermediates of formula (14-6) may then be halogenated in the presenceof a suitable halogenating agent, such as bromine, in a solvent such asacetic acid, at a temperature between 20° C. and 120° C., to obtaincompounds of formula (14-7). Compounds of formula (14-7) may then beconverted to compounds of formula (14-9) using methods described inScheme 9.

Alternatively, compounds of formula (14-4) may be halogenated to givecompounds of formula (14-5), then converted to compounds of formula(14-8) by reaction with a boronic acid, boronate ester or stannane thenconverted to compounds of formula (14-9) using similar conditions tothose described for the introduction of R³′.

Compounds (15-1) may be prepared using the methods described herein.Subjecting compounds of the general formula (15-1) to reaction withmethanesulfonyl chloride, in the presence of a base such astriethylamine, in a suitable solvent such as dichloromethane at atemperature between 0° C. and the reflux temperature of the solvent,yields compounds of formula (15-2).

Compounds of the general formula (15-3) may be obtained from compounds(15-2) by reaction with an amine, in the presence of a base such astriethylamine, in a suitable solvent such as acetonitrile at atemperature between ambient temperature and the reflux temperature ofthe solvent.

Compounds of general formula (16-3) may be prepared according to theprocedure shown in Scheme 16.

Compounds (16-1) may be prepared using the methods described in Scheme2. Subjecting compounds of the general formula (16-1) to reaction withan oxidant such as N-methylmorpholine-N-oxide, in a suitable solventsuch as tetrahydrofuran, at a temperature between ambient temperatureand the reflux temperature of the solvent, yields compound of formula(16-2).

Compounds of the general formula (16-3) may be obtained from compounds(16-2) by reaction with an alkyl halide, in the presence of a catalystsuch as copper (I) iodide, a ligand such as N,N-dimethylglycine, a basesuch as cesium carbonate in a suitable solvent such as dioxane, at atemperature between ambient temperature and reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.to 150° C.

Compounds of general formula (17-13) may be prepared according to theprocedure shown in Scheme 17.

Compounds (17-1) and (17-4) may be obtained from commercial sources orprepared using published methods described in the literature. Compoundsof general formula (17-2) may be obtained from compounds of formula(17-1) by reaction with an organometallic reagent such as a boronic acidor ester, in the presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base suchas aqueous potassium fluoride in a suitable solvent such as acetonitrileat a temperature between ambient temperature and the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 150° C.

Compounds of the general formula (17-3) may be obtained from compoundsof formula (17-2) by reaction with a base such as lithiumdiisopropylamide and a boronate source such as triisopropylborate, in asuitable solvent such as THF, at a temperature between −78° C. andambient temperature.

5-Bromo-6-chloro-4-iodo-nicotinic acid (17-5) may be obtained from5-bromo-6-chloro-nicotinic acid (17-4) by reaction with a base, such asn-butyl lithium, an amine such as 2,2,6,6-tetramethylpiperidine and aniodine source, such as solid iodine, in a suitable solvent, such as THFat a temperature between −78° C. and ambient temperature.5-Bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester(17-6) may be obtained from 5-bromo-6-chloro-4-iodo-nicotinic acid(17-5) by reaction with diphenylphosphoryl azide in the presense of abase such as triethylamine and tert-butanol, in a suitable solvent suchas toluene at a temperature between ambient temperature to refluxtemperature of the solvent. 5-Bromo-6-chloro-4-iodo-pyridin-3-ylamine(17-7) may be obtained from5-bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester(17-6) by reaction with trifluoroacetic acid in a suitable solvent suchas DCM at a temperature between −10° C. and the reflux temperature ofthe solvent.

Compounds of general formula (17-8) may be obtained from compounds offormula (17-3) by reaction with5-bromo-6-chloro-4-iodo-pyridin-3-ylamine (xiii) in the presence of atransition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base suchas aqueous potassium fluoride in a suitable solvent such as acetonitrileat a temperature from ambient temperature to the reflux temperature ofthe solvent, or under microwave irradiation at a temperature between 70°C. and 150° C.

Cyclisation of compounds with general formula (17-8) with a suitablebase such as sodium hexamethylsilazide in a suitable solvent such as THFat a temperature between 0° C. and 50° C. yields compounds of generalformula (17-9).

Compounds of the general formula (17-10) may be obtained from compounds(17-8) by reaction with an organometallic reagent such as a boronic acidor ester, in the presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base suchas aqueous potassium fluoride in a suitable solvent such as acetonitrileat a temperature between ambient temperature and the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 150° C.

Cyclisation of compounds with general formula (17-10) with a suitablebase such as sodium hexamethylsilazide in a suitable solvent such as THFat a temperature between 0° C. and 50° C. yields compounds of generalformula (17-12).

Compounds of the general formula (17-13) may be obtained from compounds(17-12) by reaction with an organometallic reagent such as a boronicacid or ester, in the presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base suchas aqueous potassium fluoride in a suitable solvent such as acetonitrileat a temperature between ambient temperature and the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 150° C.

Compounds of the general formula (17-11) may be obtained from compound(17-10) by reaction with an organometallic reagent such as a boronicacid or ester, in the presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base suchas aqueous potassium fluoride in a suitable solvent such as acetonitrileat a temperature between ambient temperature and the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 150° C.

Cyclisation of compounds with general formula (17-11) with a suitablebase such as sodium hexamethylsilazide in a suitable solvent such as THFat a temperature between 0° C. and 50° C. may give compounds of generalformula (17-13).

Compounds of formula (18-8) may be prepared using the synthetic routesoutlined in Scheme 18.

Compounds (18-1) and (18-2) may be obtained from commercial sources,prepared using published methods described in the literature, or frommethods described in Scheme 3.5-Bromo-6′-chloro-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (18-3) may beobtained from 5-bromo-2-fluoropyridine-3-boronic acid (18-2) by reactionwith 6-chloro-4-iodo-pyridin-3-ylamine (18-1) in the presence of atransition metal catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base such as aqueous sodium carbonate in asuitable solvent such as acetonitrile at a temperature between ambienttemperature and the reflux temperature of the solvent, or undermicrowave irradiation at a temperature between 70° C. to 150° C.

3-Bromo-6-chloro-1,7-diazacarbazole (18-4) may be obtained from5-bromo-6′-chloro-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (18-3) bycyclisation with a suitable base such as sodium hexamethylsilazide in asuitable solvent such as THF at a temperature between 0° C. and 50° C.

Compounds of the general formula (18-5) may be obtained from compound(18-4) by reaction with an organometallic reagent such as a boronic acidor ester, in the presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base suchas aqueous sodium carbonate in a suitable solvent such as acetonitrileat a temperature between ambient temperature and the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 150° C.

Compounds of the general formula (18-8) may be obtained from compound(18-5) by reaction with an organometallic reagent such as a boronic acidor ester, in the presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base suchas aqueous sodium carbonate in a suitable solvent such as acetonitrileat a temperature from ambient temperature to the reflux temperature ofthe solvent, or under microwave irradiation at a temperature between 70°C. to 150° C.

Compounds of the general formula (18-6) may be obtained from compound(18-3) by reaction with an organometallic reagent such as a boronic acidor ester, in the presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base suchas aqueous sodium carbonate in a suitable solvent such as acetonitrileat a temperature between ambient temperature and the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 15.0° C.

Compounds of the general formula (18-7) may be obtained from compound(18-6) by reaction with an organometallic reagent such as a boronic acidor ester, in the presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), a basesuch as aqueous sodium carbonate in a suitable solvent such asacetonitrile at a temperature between ambient temperature and the refluxtemperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 150° C.

Cyclisation of compounds with general formula (18-7) with a suitablebase such as sodium hexamethylsilazide in a suitable solvent such as THFat a temperature between 0° C. and 50° C. may give compounds of generalformula (18-8).

Compounds of formula (19-1) and (19-2) may be synthesized followingprocedures described in the literature or following the route outlinedin scheme 17. Compounds of formula (19-3) may be obtained from compoundsof formula (19-1) by reaction with a boronic acid or boronate ester offormula (19-2), in the presence of a catalyst such asbis(triphenylphosphine)palladium(II) dichloride, a base such as aqueoussodium carbonate in a suitable solvent such as acetonitrile at atemperature between room temperature and the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C. Compounds of general formula (19-3) may be cyclised toobtain compounds of formula (19-4) with a base such as sodiumhexamethyldisilazane in a suitable solvent such as TI-IF at atemperature between 0° C. and 50° C. Intermediates of formula (19-4) maythen be halogenated in the presence of a suitable halogenating agent,such as iodine monochloride, in a solvent such as acetic acid, at atemperature between 20° C. and the reflux point of the solvent, toobtain compounds of formula (19-5).

Compounds of formula (19-5) may then be converted to compounds of fomula(19-6) by reaction with a boronic acid or boronate ester (incorporatingappropriate substituents R^(3′)), in the presence of a catalyst such asbis(triphenylphosphine) palladium(II) dichloride, a base such as aqueoussodium carbonate in a suitable solvent such as acetonitrile at atemperature between room temperature and the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C. Alternatively, compounds of formula (19-5) may be coupledwith an aryl or alkyl tin compound (incorporating appropriatesubstituents R^(3′)), in the presence of a catalyst such asbis(triphenylphosphine) palladium(II) dichloride or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), with orwithout an aqueous base such as sodium carbonate, in a suitable solventsuch as acetonitrile at a temperature between room temperature and thereflux temperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 150′° C.

Compounds of formula (19-6) may be converted to compounds of formula(19-8) by reaction with an iodine source such as sodium iodide using acopper catalyst such as a combination of copper (I) iodide andN,N′-dimethylethylenediamine in a solvent such as 1,4-dioxane at atemperature between room temperature and the reflux point of thesolvent.

Compounds of formula (19-7) may be obtained from compounds of formula(19-6) and (19-8) by reaction with compounds of general formula(R^(6′)-M) by reaction with a boronic acid, boronate ester or stannaneusing similar conditions to those described previously for theintroduction of R^(3′).

Compounds of formula (20-1) may be synthesized following proceduresdescribed in the literature or following routes outlined in schemes 1,4, 10, 13, 14, 17 and 18. Compounds of formula (20-1) may be convertedto compounds of formula (20-2) by reaction with an iodine source such assodium iodide using a copper catalyst such as a combination of copper(I) iodide and N,N′-dimethylethylenediamine in a solvent such as1,4-dioxane at a temperature between room temperature and the refluxpoint of the solvent.

Compounds of formula (20-1) may also be converted to compounds ofgeneral formula (20-3) using a catalyst such as palladium in a solventsuch as ethanol under an atmosphere of hydrogen at a temperature fromroom temperature to 50° C.

Compounds of formula (21-1) may be synthesized following proceduresdescribed in the literature or following routes outlined in schemes 1,4, 10, 13, 14, 17 and 18. Compounds of formula (21-1) (where X is aleaving group such as Br or I) may be converted to compounds of formula(21-2) using a source of carbon monoxide, such as molybdenumhexacarbonyl in the presence of a catalyst such as Herman's catalyst,containing the appropriate amine (21-12) (HNR^(11′)R^(12′)), a base suchas 1,8-diazabicyclo[5,4,0]undec-7-ene in a solvent such as 1,4-dioxaneat a temperature between room temperature and the reflux point of thesolvent. Compounds of formula (21-1) may also be converted to compoundsof formula (21-3) using a source of carbon monoxide, such as molybdenumhexacarbonyl in the presence of a catalyst such as Herman's catalyst,containing the appropriate alcohol (21-13) (HOR^(11′)), a base such as1,8-diazabicyclo[5,4,0]undec-7-ene in a solvent such as 1,4-dioxane at atemperature between room temperature and the reflux point of thesolvent. Compounds of formula (21-1) may be converted to compounds offormula (21-4) using a reagent (21-14) such as zinc (II) cyanide in thepresence of a catalyst such as tetrakis(triphenylphosphine)palladium (0)in a solvent such as DMF at a temperature between room temperature andthe reflux point of the solvent, or under microwave irradiation at atemperature between 70° C. and 150° C.

Compounds of formula (21-1) may be converted to compounds of formula(21-5) using a reagent such as sodium trifluoroacetate in the presenceof a catalyst such as copper (I) iodide in a solvent such as DMF at atemperature between room temperature and the reflux point of thesolvent.

Compounds of formula (21-6) may be prepared from compounds of formula(21-1) with a base such as n-butyllithium in a solvent such as THF withthe appropriate tin halide (21-15) (where X′ is a leaving group such asCl or Br). Alternatively, compounds of formula (21-6) may be preparedfrom compounds of formula (21-1) with the appropriate alkylditin (21-16)(containing suitable R groups) in the presence of a catalyst such astetrakis(triphenylphosphine) palladium(0) in a suitable solvent such astoluene at a temperature from room temperature to the reflux temperatureof the solvent, or under microwave irradiation at a temperature between70° C. and 150° C.

Compounds of formula (21-7) may be prepared from compounds of formula(21-1) by treatment with a base such as n-butyllithium in the presenceof an alkyl borate (21-17) such as trimethyl borate in a suitablesolvent such as THF at a temperature between −78° C. and ambienttemperature. Alternatively, compounds of formula (21-7) may be preparedfrom compounds of formula (21-1) with the appropriate alkylatodiboron(21-18) in the presence of a catalyst such asbis(diphenylphosphino)ferrocene palladium(II) dichloride, using asuitable base such as potassium acetate in a solvent such as dioxane ata temperature from room temperature to the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C.

Compounds of formula (21-8) may be obtained from compounds of formula(21-1) by reaction with compounds of formula (21-19) (HSR^(9′)) in thepresence of a catalyst such as palladium (II) acetate/JOSIPHOS using abase such as potassium tert-butoxide in a suitable solvent such as DMEat a temperature from room temperature to the reflux temperature of thesolvent or solvents, or under microwave irradiation at a temperaturebetween 70° C. and 160° C.

Compounds of formula (21-9) may be obtained from compounds of formula(21-1) with a suitable alkyne (21-20) (incorporating a R^(10′) groupthat could be either maintained without modification after coupling, orthat could later be modified to give other groups)R¹⁰) by reaction inthe presence of a catalyst system such astetrakis(triphenylphosphine)palladium (0) and copper (I) iodide in thepresence of a base such as triethylamine and a suitable solvent such asN,N-dimethylformamide at a temperature between room temperature and theboiling point of the solvent. Such a coupling reaction could also becarried out in the presence of palladium on carbon, triphenylphosphine,copper (I) iodide and triethylamine in the presence of a suitablesolvent such as acetonitrile at a temperature between room temperatureand the reflux temperature of the solvent or solvents, or undermicrowave irradiation at a temperature between 70° C. and 160° C.

Compounds of formula (21-1) may be converted to compounds of formula(21-10) by reaction with a boronic acid or boronate ester (21-21)(incorporating appropriate substituents R^(3′)), in the presence of acatalyst such as bis(triphenylphosphine)palladium(II) dichloride, a basesuch as aqueous sodium carbonate in a suitable solvent such asacetonitrile at a temperature between room temperature and the refluxtemperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 150° C. Alternatively, compounds offormula (21-1) may be coupled with an aryl or alkyl tin compound (21-21)(incorporating appropriate substituents R^(3′)), in the presence of acatalyst such as bis(triphenylphosphine)palladium(II) dichloride or[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II), with orwithout an aqueous base such as sodium carbonate, in a suitable solventsuch as acetonitrile at a temperature between room temperature and thereflux temperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 150° C.

Compounds of formula (21-11) may be prepared from compounds of formula(21-6) with the appropriate halide or triflate of formula (21-22)(R^(3′)—X″), in the presence of a catalyst such astetrakis(triphenylphosphine)palladium(0) in a suitable solvent such as1,4-dioxane at a temperature from room temperature to the refluxtemperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 150° C.

Compounds of formula (21-11) may also be prepared by reaction ofcompounds of formula (21-7) with appropriate halide of formula (21-22)(R^(3′)—X″), (incorporating appropriate substituents R^(3′)), in thepresence of a catalyst such asbis(triphenylphosphine)palladium(II)dichloride, with a base such asaqueous sodium carbonate in a suitable co-solvent such as acetonitrileat a temperature from room temperature to the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C.

Compounds of formula (22-1) may be synthesized following proceduresdescribed in the literature or following routes outlined in scheme 9.Compounds of formula (22-1) may be converted to compounds of formula(22-2) by treatment with a suitable alkylating agent (22-11) R^(9′)—X orR^(22′)—X (where X is a suitable leaving group such as Cl, Br, I, OMs orOTf) using a suitable base such as cesium carbonate in a solvent suchacetonitrile at a temperature between room temperature and the refluxpoint of the solvent. Alternatively, compounds of formula (22-1) may beconverted to compounds of formula (22-3) by reaction with a suitablealdehyde (22-12) R^(9′)CHO or R^(22′)CHO and a suitable hydride sourcesuch as sodium triacetoxyborohydride in a solvent such as1,2-dichloroethane at a temperature between 0° C. and 50° C.

Compounds of formula (22-1) may also be converted to compounds offormula (22-4) using a reagent such as sodium nitrite in an acidicsolution such as aqueous hydrochloric acid, aqueous hydrobromic acid oraqueous sulfuric acid. Compounds of formula (22-4) may then be convertedto the fluoro compounds of formula (22-10) with a reagent such as sodiumtetrafluoroborate; to the chloro derivatives of formula (22-9) with areagent such as copper (I) chloride; to the iodo compounds of formula(22-8) with a reagent such as potassium iodide; the alkylthio compoundsof formula (22-7) with a reagent such as NaSR^(9′) and the cyanoderivatives (22-5) with reagents such as copper (I) cyanide andpotassium cyanide all carried out at a temperature between 0° C. and thereflux point of the solvent.

Compounds of formula (23-1) may be synthesized following proceduresdescribed in the literature or following the route outlined in scheme10. Compounds of formula (23-3), (23-4) and (−5) may be prepared usingthe synthetic route outlined in Scheme 23. Compounds of formula (23-1)may be converted to the compounds of formula (23-4) by reaction with asuitable chloride source such as phosphorus pentachloride in a suitablesolvent such as chlorobenzene at a temperature from room temperature tothe reflux point of the solvent.

Compounds of formula (23-1) may also be converted to compounds offormula (23-2) using a reagent such as nonafluorobutanesulfonicanhydride in the presence of a base such as pyridine in a suitablesolvent such as dichloromethane at a temperature between −50° C. and 20°C. Compounds of formula (23-2) may be converted to compounds of formula(23-3) by reaction with a suitable bromide source such astetra-n-butylammonium bromide in a solvent such as 1,4-dioxane at atemperature from room temperature to the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C.

Compounds of formula (23-2) may be converted to the compounds of formula(23-5) by reaction with a suitable iodide source such astetra-n-butylammonium iodide in a solvent such as 1,4-dioxane at atemperature from room temperature to the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C.

Compounds of formula (24-1) may be synthesized following proceduresdescribed in the literature or following the route outlined in scheme10. Compounds of formula (24-2) may be obtained through alkylation ofcompounds of formula (24-1) with a suitable alkylating agent (24-3)R^(11′)—X (where X is a suitable leaving group such as Cl, Br, I, OMs orOTf) using a suitable base such as cesium carbonate in a solvent such asacetonitrile at a temperature between room temperature and the refluxpoint of the solvent.

Compounds of formula (25-1) may be synthesized following proceduresdescribed in the literature or following the route outlined in scheme23. Compounds of formula (25-1) (where X is a leaving group such as Bror I) may be converted to compounds of formula (25-2) by reaction with asuitable alkenyl tin reagent of formula (25-10) such as vinyltributyltin in the presence of a transition metal catalyst such astetrakis(triphenylphosphine)palladium(0) in a suitable solvent such as1,4-dioxane at a temperature between room temperature and the refluxpoint of the solvent. Compounds of formula (25-2) may be converted tocompounds of formula (25-3) by treatment with a reagent such as ozone ina suitable solvent such as methanol at a temperature between −78° C. androom temperature followed by decomposition of the ozonide with a reagentsuch as dimethylsufide. Compounds of formula (25-3) may be converted tocompounds of formula (25-4) by reaction with a suitable amine of formula(25-11) (HNR^(16′)R^(17′)) and a suitable hydride source such as sodiumtriacetoxyborohydride in a solvent such as 1,2-dichloroethane at atemperature between 0° C. and 50° C.

Compounds of formula (25-1) (where X is a leaving group such as Br or I)may be converted to compounds of formula (25-5) by reaction with apotassium alkyl trifluoroborate or alkyl borate of formula (25-12) inthe presence of a transition metal catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloride, a basesuch as aqueous potassium carbonate in a suitable solvent such as DMF ata temperature from room temperature to the reflux temperature of thesolvent, or under microwave irradiation at a temperature between 70° C.and 150° C. Compounds of formula (25-5) may also be obtained fromcompounds of formula (25-1) by reaction with an aryl or alkyl tincompound of formula (25-12) (incorporating appropriate substituentsR^(5′)) in the presence of a catalyst such as bis(triphenylphosphine)palladium (II) dichloride or[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium (II), anaqueous base such as sodium carbonate, in a suitable solvent such asacetonitrile or combination of solvents, at a temperature between roomtemperature to the reflux temperature of the solvent, or under microwaveirradiation at a temperature between 70° C. and 150° C.

Alternatively, compounds of formula (25-7) may be obtained fromcompounds of formula (25-1) (where X is a leaving group such as Br or I)and a suitable alkyne (25-13) (incorporating a R^(10′) group that couldbe either maintained without modification after coupling, or that couldlater be modified to give other groups R¹⁰) by reaction in the presenceof a catalyst system such as tetrakis(triphenyl phosphine)palladium(0)and copper (I) iodide in the presence of a base such as triethylamineand a suitable solvent such as N,N-dimethylformamide at a temperaturebetween room temperature and the boiling point of the solvent. Such acoupling reaction could also be carried out in the presence of palladiumon carbon, triphenylphosphine, copper (I) iodide and triethylamine inthe presence of a suitable solvent such as acetonitrile at a temperaturebetween room temperature and the reflux temperature of the solvent orsolvents, or under microwave irradiation at a temperature between 70° C.and 160° C.

Compounds of formula (25-1) (where X is a leaving group such as F, Cl,Br or I) may be converted to compounds of formula (25-6) by displacementwith a suitable amine of formula (25-11) (HNR^(11′)R^(12′)) either assolvent or in a solvent such as NMP at a temperature between ambienttemperature and the reflux point of the solvent. Compounds of formula(25-3) may also be obtained from compounds of formula (25-1) (where X isa leaving group such as Br or I) by reaction with compounds of formula(25-11) (HNR^(11′)R^(12′)) in the presence of a catalyst such as[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II), in thepresence of a base such as potassium tert-butoxide in a suitable solventsuch as DME, or a mixture of two or more appropriate solvents, at atemperature from room temperature to the reflux temperature of thesolvent or solvents, or under microwave irradiation at a temperaturebetween 70° C. and 160° C.

Compounds of formula (25-8) may be obtained from compounds of formula(25-1) (where X is a leaving group such as Br or I) by reaction withcompounds of general formula (25-14) (HSR^(11′)) in the presence of acatalyst such as palladium(II) acetate/JOSIPHOS in the presence of abase such as potassium tert-butoxide in a suitable solvent such as DME,or a mixture of two or more appropriate solvents, at a temperature fromroom temperature to the reflux temperature of the solvent or solvents,or under microwave irradiation at a temperature between 70° C. and 160°C.

The sulfide intermediates of formula (25-8) may be converted tosulfoxides and sulfones of formula (25-9) by oxidation with a suitableoxidizing agent such as oxone in a solvent such as acetone at atemperature between 0° C. and 50° C.

Compounds of formula (26-1) may be synthesized following proceduresdescribed in the literature or following the route outlined in scheme10. Compounds of formula (26-1) may be converted to compounds of formula(26-2) by treatment with an acid such as hydrochloric acid in a solventsuch as water at a temperature between room temperature and the refluxpoint of the solvent, or in a sealed vessel at a temperature between 70°C. and 140° C.

Compounds of formula (26-2) may then be reacted with an appropriatealcohol (26-10) (R^(11′)OH) using a phosphine and a coupling reagentsuch as diisopropylazodicarboxylate in an appropriate solvent such asTHF to provide ethers of general formula (26-3). Alternatively,compounds of formula (26-3) may be obtained through alkylation ofcompounds of general formula (26-2) with a suitable alkylating agent(26-11) R^(11′)—X (where X is a suitable leaving group such as Cl, Br,I, OMs or OTO using a suitable base such as cesium carbonate in asolvent such as acetonitrile at a temperature between room temperatureand the reflux point of the solvent.

Compounds of formula (26-2) may also be converted to the nonaflates(26-5) using a reagent such as nonafluorobutanesulfonic anhydride in thepresence of a base such as pyridine in a suitable solvent such asdichloromethane at a temperature between −50° C. and 20° C.

Compounds of formula (26-5) may be converted to compounds of formula(26-4) by displacement with a suitable amine of general formula (26-12)(HNR^(11′)R^(12′)) either as solvent or in a solvent such as NMP at atemperature between ambient temperature and the reflux point of thesolvent. Compounds of formula (26-4) may also be obtained from compoundsof formula (26-5) by reaction with compounds of general formula (26-12)(HNR^(11′)R^(12′)) in the presence of a catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in thepresence of a base such as potassium tert-butoxide in a suitable solventsuch as DME, or a mixture of two or more appropriate solvents, at atemperature from room temperature to the reflux temperature of thesolvent or solvents, or under microwave irradiation at a temperaturebetween 70° C. and 160° C.

Alternatively, compounds of formula (26-7) may be obtained fromcompounds of formula (26-5) with a suitable alkyne (26-14)(incorporating a R^(10′) group that could be either maintained withoutmodification after coupling, or that could later be modified to giveother groups R¹⁰) by reaction in the presence of a catalyst system suchas tetrakis(triphenylphosphine)palladium (0) and copper (I) iodide inthe presence of a base such as triethylamine and a suitable solvent suchas N,N-dimethylformamide at a temperature between room temperature andthe boiling point of the solvent. Such a coupling reaction could also becarried out in the presence of palladium on carbon, triphenylphosphine,copper (I) iodide and triethylamine in the presence of a suitablesolvent such as acetonitrile at a temperature between room temperatureand the reflux temperature of the solvent or solvents, or undermicrowave irradiation at a temperature between 70° C. and 160° C.

The nonaflate intermediates (26-5) may be converted to compounds offormula (26-8) by reaction with a potassium alkyl trifluoroborate oralkyl borate of formula (26-15) in the presence of a transition metalcatalyst such as [1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloride, a base such as aqueous potassium carbonate in a suitablesolvent such as DMF at a temperature from room temperature to the refluxtemperature of the solvent, or under microwave irradiation at atemperature between 70° C. and 150° C. Compounds of general formula(26-8) may also be obtained from compounds of formula (26-5) by reactionwith an aryl or alkyl tin compound (incorporating appropriatesubstituents R^(5′)), in the presence of a catalyst such asbis(triphenylphosphine)palladium (II) dichloride or[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), an aqueousbase such as sodium carbonate, in a suitable solvent such asacetonitrile or combination of solvents, at a temperature between roomtemperature to the reflux temperature of the solvent, or under microwaveirradiation at a temperature between 70° C. and 150° C.

Compounds of formula. (26-6) may be obtained from compounds of formula(26-5) (where X is a leaving group such as Br or I) by reaction withcompounds of formula (26-13) (HSR^(11′)) in the presence of a catalystsuch as palladium (II) acetate/JOSIPHOS in the presence of a base suchas potassium tert-butoxide in a suitable solvent such as DME, or amixture of two or more appropriate solvents, at a temperature from roomtemperature to the reflux temperature of the solvent or solvents, orunder microwave irradiation at a temperature between 70° C. and 160° C.

The sulfide intermediates of formula (26-6) may be converted tosulfoxides and sulfones of formula (26-9) by oxidation with a suitableoxidizing agent such as oxone in a solvent such as acetone at atemperature between 0° C. and 50° C.

Scheme 27

Compounds of formula (27-4) may be synthesized following proceduresdescribed in the literature or by the method outlined in Scheme 27-1.Compound (27-1) may be converted to compound (27-2) by treatment withammonia in a suitable solvent such as methanol by heating in a sealedvessel at a temperature up to 150Error! Not a valid link.C. Compound(27-2) may be converted to compound (27-3) by treatment with adehydrating agent in a suitable solvent at an appropriate temperature,such as trifluoroacetic acid anhydride in the presence of triethylamineat between 0Error! Not a valid link.0 and ambient temperature. Compound(27-3) may be converted to protected compounds of formula (27-4) byliterature methods wherein P′ represents a suitable protecting group,such as the 2-trimethylsilanylethoxy methyl derivative by treatment with2-trimethylsilanylethoxymethyl chloride and sodium hydride intetrahydrofuran.

Compounds of formula (27-4) may also be synthesized from compounds offormula (27-5) as outlined in Scheme 27-2, by a literature or otherreduction method, such as by hydrogenation in the presence of acarbon-supported palladium catalyst in a suitable solvent such astetrahydrofuran, or by treatment with zinc powder and ammonium formatein tetrahydrofuran.

Compounds of formula (27-10) may be synthesized from compounds offormula (27-4) as outlined in Scheme 27-2. Compounds of the formula(27-4) may be converted to compounds of formula (27-6) by treatment withan oxidant in a suitable solvent, such as urea-hydrogen peroxide adductand Error! Not a valid link.in chloroform at ambient temperature.Compounds (27-6) may be converted to compounds (27-7) by treatment withan electrophilic agent and chloride source, such as methanesulfonylchloride in N,N-dimethylformamide at ambient temperature. Compounds(27-7) may be deoxygenated to compounds (27-8) by treatment with asuitable reducing agent, such as triethylamine in the presence of[1,1′-bis(diphenyl phosphino)ferrocene]dichloropalladium(II) inacetonitrile under microwave irradiation.

Compounds of formula (27-8) may also be synthesized by the methodoutlined in scheme 27-3. Compounds (27-4) may also be converted tocompounds of formula (27-11) by treatment with an oxidant in a suitablesolvent, such as urea-hydrogen peroxide adduct and Error! Not a validlink.in chloroform. Compounds (27-11) may be converted to compounds(27-8) by treatment with a suitable agent such as methanesulfonylchloride in N,N-dimethylformamide at ambient temperature.

Compounds of formula (27-8) may be converted to compounds of formula(27-9) by treatment with an alcohol, represented by R⁹OH, in thepresence of a suitable base such as sodium hydride, in a suitablesolvent such as tetrahydrofuran, at a temperature between ambienttemperature and the boiling point of the solvent, or at a temperature inexcess of the boiling point of the solvent in a sealed vessel. Compoundsof formula (27-9) may be converted to compounds (27-10) by removal ofthe protecting group represented by P¹, such as the2-trimethylsilanylethoxymethyl protecting group, for example bytreatment with tetrabutylammonium fluoride in tetrahydrofuran, or as afurther example by treatment with aqueous hydrobromic acid in dioxanefollowed by treatment with aqueous sodium hydroxide.

It will be appreciated that where appropriate functional groups exist,compounds described in the formulae of Schemes 1-27 or any intermediatesused in their preparation may be further derivatised by one or morestandard synthetic methods employing substitution, oxidation, reduction,or cleavage reactions. Particular substitution approaches includeconventional alkylation, arylation, heteroarylation, acylation,sulfonylation, halogenation, nitration, formylation and couplingprocedures.

In a further example primary amine (—NH₂) groups may be alkylated usinga reductive alkylation process employing an aldehyde or a ketone and aborohydride, for example sodium triacetoxyborohydride or sodiumcyanoborohydride, in a solvent such as a halogenated hydrocarbon, forexample 1,2-dichloroethane, or an alcohol such as ethanol, wherenecessary in the presence of an acid such as acetic acid at aroundambient temperature. Secondary amine (—NH—) groups may be similarlyalkylated employing an aldehyde.

In a further example, primary amine or secondary amine groups may beconverted into amide groups (—NHCOR′ or —NRCOR′) by acylation. Acylationmay be achieved by reaction with an appropriate acid chloride in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dichloromethane, or by reaction with an appropriate carboxylic acidin the presence of a suitable coupling agent such HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in a suitable solvent such as dichloromethane.Similarly, amine groups may be converted into sulphonamide groups(—NHSO₂R′ or —NR″SO₂R′) groups by reaction with an appropriate sulphonylchloride in the presence of a suitable base, such as triethylamine, in asuitable solvent such as dichloromethane. Primary or secondary aminegroups can be converted into urea groups (—NHCONR′R¹¹ or —NRCONR′R″) byreaction with an appropriate isocyanate in the presence of a suitablebase such as triethylamine, in a suitable solvent, such asdichloromethane.

An amine (—NH₂) may be obtained by reduction of a nitro (—NO₂) group,for example by catalytic hydrogenation, using for example hydrogen inthe presence of a metal catalyst, for example palladium on a supportsuch as carbon in a solvent such as ethyl acetate or an alcohol e.g.methanol. Alternatively, the transformation may be carried out bychemical reduction using for example a metal, e.g. tin or iron, in thepresence of an acid such as hydrochloric acid.

In a further example, amine (—CH₂NH₂) groups may be obtained byreduction of nitriles (—CN), for example by catalytic hydrogenationusing for example hydrogen in the presence of a metal catalyst, forexample palladium on a support such as carbon, or Raney nickel, in asolvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, ata temperature from −78° C. to the reflux temperature of the solvent.

In a further example, amine (—NH₂) groups may be obtained fromcarboxylic acid groups (—CO₂H) by conversion to the corresponding acylazide (—CON₃), Curtius rearrangement and hydrolysis of the resultantisocyanate (—N═C═O).

Aldehyde groups (—CHO) may be converted to amine groups (—CH₂NR′R″)) byreductive amination employing an amine and a borohydride, for examplesodium triacetoxyborohydride or sodium cyanoborohydride, in a solventsuch as a halogenated hydrocarbon, for example dichloromethane, or analcohol such as ethanol, where necessary in the presence of an acid suchas acetic acid at around ambient temperature.

In a further example, aldehyde groups may be converted into alkenylgroups (—CH═CHR′) by the use of a Wittig or Wadsworth-Emmons reactionusing an appropriate phosphorane or phosphonate under standardconditions known to those skilled in the art.

Aldehyde groups may be obtained by reduction of ester groups (such as—CO₂Et) or nitriles (—CN) using diisobutylaluminium hydride in asuitable solvent such as toluene. Alternatively, aldehyde groups may beobtained by the oxidation of alcohol groups using any suitable oxidisingagent known to those skilled in the art.

Ester groups (—CO₂R′) may be converted into the corresponding acid group(—CO₂H) by acid- or base-catalused hydrolysis, depending on the natureof R. If R is t-butyl, acid-catalysed hydrolysis can be achieved forexample by treatment with an organic acid such as trifluoroacetic acidin an aqueous solvent, or by treatment with an inorganic acid such ashydrochloric acid in an aqueous solvent.

Carboxylic acid groups (—CO₂H) may be converted into amides (CONHR′ or—CONR′R″) by reaction with an appropriate amine in the presence of asuitable coupling agent, such as HATU, in a suitable solvent such asdichloromethane.

In a further example, carboxylic acids may be homologated by one carbon(i.e —CO₂H to —CH₂CO₂H) by conversion to the corresponding acid chloride(—COCl) followed by Arndt-Eistert synthesis.

In a further example, —OH groups may be generated from the correspondingester (e.g. —CO₂R′), or aldehyde (—CHO) by reduction, using for examplea complex metal hydride such as lithium aluminium hydride in diethylether or tetrahydrofuran, or sodium borohydride in a solvent such asmethanol. Alternatively, an alcohol may be prepared by reduction of thecorresponding acid (—CO₂H), using for example lithium aluminium hydridein a solvent such as tetrahydrofuran, or by using borane in a solventsuch as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as halogenatoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. p-toluenesulfonyloxygroup using conditions known to those skilled in the art. For example,an alcohol may be reacted with thioyl chloride in a halogenatedhydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.A base (e.g. triethylamine) may also be used in the reaction.

In another example, alcohol, phenol or amide groups may be alkylated bycoupling a phenol or amide with an alcohol in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl-, diisopropyl, ordimethylazodicarboxylate. Alternatively alkylation may be achieved bydeprotonation using a suitable base e.g. sodium hydride followed bysubsequent addition of an alkylating agent, such as an alkyl halide.

Aromatic halogen substituents in the compounds may be subjected tohalogen-metal exchange by treatment with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g. around −78° C., in a solvent such as tetrahydrofuran,and then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing N,N-dimethylformamide as the electrophile. Aromatic halogensubstituents may alternatively be subjected to metal (e.g. palladium orcopper) catalysed reactions, to introduce, for example, acid, ester,cyano, amide, aryl, heteraryl, alkenyl, alkynyl, thio- or aminosubstituents. Suitable procedures which may be employed include thosedescribed by Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogen substituents may also undergo nucleophilic displacementfollowing reaction with an appropriate nucleophile such as an amine oran alcohol. Advantageously, such a reaction may be carried out atelevated temperature in the presence of microwave irradiation.

The compounds of the present invention are tested for their capacity toinhibit chk1 activity and activation (primary assays) and for theirbiological effects on growing cells (secondary assays) as describedbelow. The compounds having IC₅₀ of less than 10 μM (more preferablyless than 5 μM, even more preferably less than 1 μM, most preferablyless than 0.5 μM) in the chk1 activity and activation assay of Examplei, and EC₅₀ of less than 10 μM (more preferably less than 5 μM, mostpreferably less than 1 μM) in the cellular assay of Example ii, areuseful as chk1 inhibitors.

The present invention includes a composition (e.g., a pharmaceuticalcomposition) comprising a compound of Formula (I), (I-a) and/or (I-b),(and/or solvates, hydrates and/or salts thereof) and a carrier (apharmaceutically acceptable carrier). The present invention alsoincludes a composition (e.g., a pharmaceutical composition) comprising acompound of Formula (I), (I-a) and/or (I-b) (and/or solvates, hydratesand/or salts thereof) and a carrier (a pharmaceutically acceptablecarrier), further comprising a second chemotherapeutic agent such asthose described herein. The present invention also includes acomposition (e.g., a pharmaceutical composition) comprising a compoundof Formula (I), (I-a) and/or (I-b) (and/or solvates, hydrates and/orsalts thereof) and a carrier (a pharmaceutically acceptable carrier),further comprising a second chemotherapeutic agent such as a DNAdamaging agent including those described herein. The presentcompositions are useful for inhibiting abnormal cell growth or treatinga hyperproliferative disorder such as cancer in a mammal (e.g., human).For example, the present compounds and compositions are useful fortreating breast cancer, colorectal cancer, ovarian cancer, non-smallcell lung cancer, malignant brain tumors, sarcomas, melanoma, lymphoma,myelomas and/or leukemia in a mammal (e.g., human).

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder such as cancer in amammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula (I), (I-a)and/or (I-b) (and/or solvates, hydrates and/or salts thereof) or acomposition thereof. For example, the present invention includes amethod of treating breast cancer, colorectal cancer, ovarian cancer,non-small cell lung cancer, malignant brain tumors, sarcomas, melanoma,lymphoma, myelomas and/or leukemia in a mammal (e.g., human), comprisingadministering to said mammal a therapeutically effective amount of acompound of Formula (I), (I-a) and/or (I-b) (and/or solvates, hydratesand/or salts thereof) or a composition thereof.

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder such as cancer in amammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula (I), (I-a)and/or (I-b) (and/or solvates, hydrates and/or salts thereof) or acomposition thereof, in combination with a second chemotherapeutic agentsuch as those described herein. The present invention also includes amethod of inhibiting abnormal cell growth or treating ahyperproliferative disorder such as cancer in a mammal (e.g., human)comprising administering to said mammal a therapeutically effectiveamount of a compound of Formula (I), (I-a) and/or (I-b) (and/orsolvates, hydrates and/or salts thereof) or a composition thereof, incombination with a second chemotherapeutic agent such as a DNA damagingagent including those described herein. For example, the presentinvention includes a method of treating breast cancer, colorectalcancer, ovarian cancer, non-small cell lung cancer, malignant braintumors, sarcomas, melanoma, lymphoma, myelomas and/or leukemia in amammal (e.g., human), comprising administering to said mammal atherapeutically effective amount of a compound of Formula (I), (I-a)and/or (I-b) (and/or solvates, hydrates and/or salts thereof) or acomposition thereof, in combination with a second chemotherapeutic agentsuch as those described herein. The present invention also includes amethod of treating breast cancer, colorectal cancer, ovarian cancer,non-small cell lung cancer, malignant brain tumors, sarcomas, melanoma,lymphoma, myelomas and/or leukemia in a mammal (e.g., human), comprisingadministering to said mammal a therapeutically effective amount of acompound of Formula (I), (I-a) and/or (I-b) (and/or solvates, hydratesand/or salts thereof) or a composition thereof, in combination with asecond chemotherapeutic agent such as such as a DNA damaging agentincluding those described herein.

The present invention includes a method of using the present compoundsfor in vitro, in situ, and in vivo diagnosis or treatment of mammaliancells, organisms, or associated pathological conditions.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, inhalation and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to 7 g/day,preferably about 0.05 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or in combinationwith one or more chemotherapeutic agents, for example those describedherein. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof treatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic.acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

EXAMPLES Abbreviations

-   ACN Acetonitrile-   AIBN 2,2′-Azobis(2-methylproprionitrile)-   ATP Adenosine-5′-triphosphate-   Biotage Pre-packed silica Biotage® SNAP Cartridge for flash    chromatography-   t-BME t-Butyl methyl ether-   CDCl₃ Deuterated chloroform-   DCM Dichloromethane-   DIPEA Diisopropylethylamine-   DMAP 4-Dimethylaminopyridine-   DME 1,2-Dimethoxyethane-   DMF Dimethylformamide-   DMSO Dimethylsulfoxide-   DMSO-d₆ Deuterated dimethylsulfoxide-   EtOAc Ethyl acetate-   EtOH Ethanol-   h Hour-   HCl Hydrochloric acid-   HM-N Isolute® HM-N is a modified form of diatomaceous earth that can    efficiently absorb aqueous samples-   HOBt 1-Hydroxybenzotriazole-   IMS Industrial methylated spirits-   LDA Lithium diisopropylamide-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl    uroniumhexafluorophosphate-   LCMS Liquid Chromatography Mass Spectroscopy-   LDA Lithium diisopropylamide-   MeOH Methanol-   mmol Millimoles-   mol Moles-   N Normal (concentration)-   NaHCO₃ Sodium bicarbonate-   NaOH Sodium hydroxide-   NBS N-Bromosuccinimide-   NMR Nuclear magnetic resonance-   PyBOP (Benzotriazol-1-yloxy)tripyrrolidinophosphonium    hexafluorophosphate-   SCX-2 Strong cationic exchange resin-   Si-SPE Pre-packed Isolute® silica flash chromatography cartridge-   Si-ISCO Pre-packed ISCO® silica flash chromatography cartridge-   THF Tetrahydrofuran-   TFA Trifluoroacetic acid-   TLC Thin layer chromatography-   TMS Trimethylsilyl

General Experimental Conditions

¹H NMR spectra were recorded at ambient temperature using a Varian UnityInova (400 MHz):spectrometer with a triple resonance 5 mm probe.Chemical shifts are expressed in ppm relative to tetramethylsilane. Thefollowing abbreviations have been used: br=broad signal, s=singlet,d=doublet, dd=double doublet, t=triplet, q=quartet, m=multiplet.

High Pressure Liquid Chromatography—Mass Spectrometry (LCMS) experimentsto determine retention times (R_(T)) and associated mass ions wereperformed using one of the following Methods.

Method A: Experiments performed on a Waters Micromass ZQ quadrupole massspectrometer linked to a Hewlett Packard HP 1100 LC system with diodearray detector. This system uses a Higgins Clipeus 5 micron C18 100×3.0mm column and a 1 ml/minute flow rate. The initial solvent system was95% water containing 0.1% formic acid (solvent A) and 5% acetonitrilecontaining 0.1% formic acid (solvent B) for the first minute followed bya gradient up to 5% solvent A and 95% solvent B over the next 14minutes. The final solvent system was held constant for a further 5minutes.

Method B: Experiments performed on a Waters Platform LC quadrupole massspectrometer linked to a Hewlett Packard HP1100 LC system with diodearray detector and 100 position autosampler using a Phenomenex LunaC18(2) 30×4.6 mm column and a 2 ml/minute flow rate. The solvent systemwas 95% water containing 0.1% formic acid (solvent A) and 5%acetonitrile containing 0.1% formic acid (solvent B) for the first 0.50minutes followed by a gradient up to 5% solvent A and 95% solvent B overthe next 4 minutes. The final solvent system was held constant for afurther 0.50 minutes.

Method C: Experiments performed on a Shimadzu LCMS-2010EV liquidchromatography mass spectrometer linked to a Shimadzu LC-20AB LC systemwith diode array detector. Uses a Shim-pack XR-ODS 2.2 micron 30×3.0 mmcolumn and a 1.2 ml/minute flow rate. The initial solvent system was 10%water containing 0.038% trifluoroacetic acid (solvent A) and 90%acetonitrile containing 0.019% trifluoroacetic acid (solvent B),followed by a gradient up to 80% solvent A and 90% solvent B over 2minutes.

Method D: Experiments performed on an Agilent 1100 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an Agilent ZORBAXSB-C 18 100×3.0 mm column and a 0.7 ml/minute flow rate. The solventsystem was a gradient starting with 95% water with 0.05% TFA (solvent A)and 5% acetonitrile with 0.05% TFA (solvent B), ramping up to 5% solventA and 95% solvent B over 25 minutes. The final solvent system was heldconstant for a further 5 minutes.

Method E: Experiments performed on an Agilent 1100 HPLC with Agilent MSDmass spectrometer using ESI as ionization source using an Agilent ZORBAXSB-C 18 30×2.1 mm column and a 0.6 ml/minute flow rate. The solventsystem was a gradient starting with 95% water with 0.05% TFA (solvent A)and 5% acetonitrile with 0.05% TFA (solvent B), ramping up to 5% solventA and 95% solvent B over 9 minutes. The final solvent system was heldconstant for a further 1 minute.

Method F: Experiments performed on a Waters Micromass ZQ2000 quadrupolemass spectrometer using ESI as ionization source using a Higgins Clipeus5 micron C18 100×3.0 mm column and a 1 ml/minute flow rate. The solventsystem was a gradient starting with 85% water with 0.1% formic acid(solvent A) and 15% methanol with 0.1% formic acid (solvent B), rampingup to 5% solvent A and 95% solvent B over 12 minutes. The final solventsystem was held constant for a further 1 minute.

Method G: Experiments performed on a Waters Platform LC quadrupole massspectrometer linked to a Hewlett Packard HP1100 LC system with diodearray detector and 100 position autosampler using a Phenomenex LunaC18(2) 30×4.6 mm column and a 2 ml/minute flow rate. The solvent systemwas 95% water containing 0.1% formic acid (solvent A) and 5% methanolcontaining 0.1% formic acid (solvent B) for the first 0.50 minutesfollowed by a gradient up to 5% solvent A and 95% solvent B over thenext 4 minutes. The final solvent system was held constant for a further0.50 minutes.

Method H: Experiments performed on a Waters Quattro Micro triplequadrupole mass spectrometer using ESI as ionization source using aHiggins Clipeus 5 micron C18 100×3.0 mm column and a 1 ml/minute flowrate. The solvent system was a gradient starting with 85% water with0.1% formic acid (solvent A) and 15% methanol with 0.1% formic acid(solvent B), ramping up to 5% solvent A and 95% solvent B over 12minutes. The final solvent system was held constant for a further 1minute.

Microwave experiments were carried out using a Biotage Initiator 60™which uses a single-mode resonator and dynamic field tuning. Temperaturefrom 40-250° C. can be achieved, and pressures of up to 30 bar can bereached. Alternatively, a CEM Discover microwave was also used for someof the experiments.

Unless specified, typically preparative HPLC purification refers to theuse of an Xbridge™ Prep C18 10 μm OBD™ 19×100 mm column or a similar C18column unless stated otherwise. Methods are generally run on a gradientof 5-85% acetonitrile/water modified with either 0.1% formic acid or0.1% ammonium hydroxide over 20 minutes at a flow rate of 35 mL/min.

General Methods

Boronic acids and boronate esters were prepared from the appropriatearyl halide intermediate by using the general coupling methods describedbelow. All aryl halide intermediates were either commercially available,prepared using literature methods or could be readily prepared by thoseskilled in the art. In some cases the intermediate was not isolated, andthe coupling reaction performed on the crude boronic acid/boronateester. Suzuki reactions were performed using either commerciallyavailable boronic acids/boronate esters or from compounds prepared usingthe procedures detailed below. If necessary, any protecting groups werethen removed using one of the deprotection conditions described below.Stille reactions were performed using either commercially availablestannanes or from compounds prepared using the procedures detailedbelow. If necessary, any protecting groups were then removed using oneof the deprotection conditions described below.

General Methylation of Piperidine Derivative Method

The appropriate BOC-protected/HCl salt/free amine piperidine derivative(1-2 eq.) was dissolved in a solution of aqueous formaldehyde in formicacid, and the mixture was heated with microwave irradiation (100-160°C.) for between 5 and 15 minutes. The resultant residue was loaded ontoan Isolute® SCX-2 cartridge. The cartridge was then washed withacetonitrile before the desired product was eluted using 2M ammonia inMeOH.

General Mesylate Displacement Methods

Method A: A mixture of6-cyano-3-(4-methanesulfonyloxymethyl-phenyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylicacid tert-butyl ester (1 eq.), amine (1.1-1.5 eq.) and triethylamine(1.1-1.5 eq.) in acetonitrile was stirred between ambient temperatureand 50° C. until analysis (TLC/LCMS) showed complete consumption ofstarting material. The reaction mixture was allowed to cool to ambienttemperature and was then partitioned between ethyl acetate and water.The organic layer was separated, dried over anhydrous sodium sulfate,filtered and evaporated in vacuo. The resultant residue was subjected topurification by one of the general methods described below.

Method B: A mixture of methanesulfonic acid4-[6-cyano-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl]-benzylester (1 eq.), amine (1.1-1.5 eq.) and triethylamine (1.1-1.5 eq.) inacetonitrile was stirred between ambient temperature and 50° C. untilanalysis (TLC/LCMS) showed complete consumption of starting material.The reaction mixture was allowed to cool to ambient temperature and wasthen partitioned between ethyl acetate and water. The organic layer wasseparated, dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo. The resultant residue was subjected first to deprotection, andthen purification, by the general methods described below.

Method C: A mixture of methanesulfonic acid4-[6-cyano-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl]-benzylester (1 eq.), amine (1.1-1.5 eq.) and triethylamine (1.1-1.5 eq.) inacetonitrile was heated with microwave irradiation (100-150-° C.) forbetween 1 and 30 minutes until analysis (TLC/LCMS) showed completeconsumption of starting material. The reaction mixture was allowed tocool to ambient temperature and was then partitioned between ethylacetate and water. The organic layer was separated, dried over anhydroussodium sulfate, filtered and evaporated in vacuo. The resultant residuewas subjected first to deprotection, and then purification, by thegeneral methods described below.

Method D:9-Benzenesulfonyl-5-(3-chloropropyl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) was treated with a large excess of the amine (50-300 eq.) andthe mixture was heated with microwave irradiation (between 90° C. and140° C.) for between 1 and 30 minutes until analysis (TLC/LCMS) showedcomplete consumption of starting material. The reaction mixture wasallowed to cool to ambient temperature and was then subjected topurification by the general methods described below.

Method E: Methanesulfonic acid3-[9-benzenesulfonyl-6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yl]-propylester (1 eq.) was treated with a large excess of the amine (50-300 eq.)and the mixture was heated with microwave irradiation (between 90° C.and 140° C.) for between 1 and 30 minutes until reaction was deemedcomplete. The reaction mixture was allowed to cool to ambienttemperature and was then subjected to purification by the generalmethods described below.

Method F: A mixture of9-benzenesulfonyl-3-(1-methyl-1H-pyrazol-4-yl)-5-piperidin-4-ylmethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), alkyl halide (1.1-1.5 eq.) and triethylamine (1.1-1.5 eq.) inacetonitrile was heated at reflux for between 5 and 60 minutes until thereaction was deemed complete. The reaction mixture was allowed to coolto ambient temperature and was then subjected to purification by thegeneral methods described below.

General Boronic Acid/Boronate Ester Preparation Method

Method A: The appropriate aryl halide (1-3 eq.) was suspended in amixture of THF under an inert atmosphere then n-butyl lithium (1-3 eq.)was added at −78° C. After between 5 and 30 minutes at this temperature,trialkylborate (1-3 eq.) was added then the reaction mixture was warmedto ambient temperature and quenched by the addition of ammoniumchloride. The resultant residue was purified by one of the generalpurification methods described below or used crude in the next step.

Method B: The appropriate aryl halide (1-3 eq.) was suspended in amixture of dioxane and DMSO before bis(pinacolato)diboron (1-2 eq.),potassium acetate and1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (5-10 mol %)were added and the reaction mixture was then heated with microwaveirradiation (100-160° C.) for between 1 and 20 minutes. The resultantresidue was purified by one of the general purification methodsdescribed below or used crude in the next step.

Method C: The appropriate (bromomethyl)phenyl boronic acid (1 eq.) wasstirred with sodium iodide (0.05 eq.) and potassium carbonate (3.0 eq.)in acetonitrile and the appropriate amine (1.2 eq.) added. The mixturewas heated to 50° C. for 2 h and then cooled to ambient temperature orstirred at room temperature until reaction complete, then the volatilecomponents were removed in vacuo and the residue re-suspended in MeOH.The remaining solid was removed by filtration then the methanolicsolution was collected and concentrated to dryness under reducedpressure. The resulting boronic acid was used with no furtherpurification.

Method D: The appropriate electrophile (1-2 eq.) and potassium carbonate(3-5 eq.) were added to4,4,5,5-tetramethyl-2(1H-pyrazol-4-yl)-1,3,2-dioxaborolane inacetonitrile and the mixture was stirred under reflux for between 1 and7 days. The residue was purified by one of the general purificationmethods described below.

General Suzuki Coupling Method

Method A: The appropriate boronic acid/boronate ester/triflate (1-3 eq.)was suspended in acetonitrile before3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile or3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), aqueous sodium carbonate solution andbis(triphenylphosphine)palladium(II) dichloride (5-10 mol %) were addedand the reaction mixture was then heated with microwave irradiation(100-160° C.) for between 1 and 30 minutes. The resultant residue waspurified by one of the general purification methods described below.

Method B: The appropriate boronic acid/boronate ester (1-3 eq.) wassuspended in a mixture of dioxane and DMSO before3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile or3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), aqueous potassium acetate solution and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10 mol %)were added and the reaction mixture was then heated with microwaveirradiation (100-160° C.) for between 1 and 20 minutes. The resultantresidue was purified by one of the general purification methodsdescribed below.

Method C: The appropriate boronic acid/boronate ester (1-3 eq.) wassuspended in DME before3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile or3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), aqueous cesium carbonate solution and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10 mol %)were added and the reaction mixture was then heated with microwaveirradiation (100-160° C.) for between 1 and 20 minutes. The resultantresidue was purified by one of the general purification methodsdescribed below.

Method D: The appropriate boronic acid/boronate ester (1-3 eq.) wassuspended in acetonitrile before3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile or3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), aqueous sodium carbonate solution or potassium fluoridesolution, and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10 mol %)were added and the reaction mixture was then heated with microwaveirradiation (100-160° C.) for between 1 and 30 minutes. The resultantresidue was purified by one of the general purification methodsdescribed below.

Method E: The appropriate boronic acid/boronate ester (1-3 eq.) wassuspended in DME/IMS before3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile or3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), aqueous cesium carbonate solution andtetrakis(triphenylphosphine)palladium(0) (5-10 mol %) were added, andthe reaction mixture was heated with microwave irradiation (100-160° C.)for between 1 and 30 minutes. The resultant mixture was purified by oneof the general purification methods described below.

Method F:3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile wassuspended in acetonitrile before the appropriate aryl/heteroharylbromide (1-3 eq.), aqueous sodium carbonate or potassium fluoridesolution solution and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10 mol %)were added and the reaction mixture was then heated with microwaveirradiation (100-160° C.) for between 1 and 60 minutes. The resultantmixture was purified by one of the general purification methodsdescribed below.

Method G: The appropriate aryl halide (1-3 eq.) was suspended in DME/IMSbefore3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), aqueous cesium carbonate solution andtetrakis(triphenylphosphine)palladium(0) (5-10 mol %) were added and thereaction mixture was then heated with microwave irradiation (100-160°C.) for between 1 and 30 minutes. The resultant mixture was purified byone of the general purification methods described below.

Method H: The appropriate aryl halide (1-3 eq.) was suspended inacetonitrile before3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1 eq.),aqueous sodium carbonate solution andbis(triphenylphosphine)palladium(II) dichloride (5-10 mol %) were addedand the reaction mixture was then heated with microwave irradiation(100-160° C.) for between 1 and 30 minutes. The resultant mixture waspurified by one of the general purification methods described below.

Method I: The appropriate boronic acid/boronate ester (1.5 eq.) wassuspended in DMF before6-chloro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(1.5 eq.), aqueous sodium carbonate solution andtetrakis(triphenylphosphine)palladium(0) (5 mol %) were added and thereaction mixture was then heated with microwave irradiation (140° C.)for 60-90 minutes. The resultant mixture was purified by one of thegeneral purification methods described below.

Method J: The appropriate boronic acid/boronate ester (1.5 eq.) wassuspended in acetonitrile before6-chloro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(1.5 eq.), aqueous potassium carbonate solution and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mol %)were added and the reaction mixture was then heated with microwaveirradiation (140° C.) for 60 minutes. The resultant mixture was purifiedby one of the general purification methods described below.

Method K: The appropriate aryl triflate (1-3 eq.) was suspended inDME/IMS before3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), aqueous cesium carbonate solution and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10 mol %)were added and the reaction mixture was then heated with microwaveirradiation (100-160° C.) for between 1 and 30 minutes.

Method L:9-Benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) was suspended in tetrahydrofuran before the appropriatepotassium alkylhalide trifluoroborate (2 eq.), aqueous sodium carbonateor potassium fluoride solution solution and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5-10 mol %)were added and the reaction mixture was refluxed for 16 hours. Thereaction mixture was allowed to cool to ambient temperature and was thenpartitioned between THF and brine. The organic layer was separated,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo.The resultant residue was subjected to purification, by the generalmethods described below.

Method M: A mixture of 4-methylenepiperidine-1-carboxylic acidtert-butyl ester (1 eq.) and 9-borabicyclo[3.3.1]nonane (1 eq.) washeated to reflux for 1 hour before it was added to a degassed suspensionof9-benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1-3 eq.), aqueous sodium carbonate or potassium fluoride solutionsolution and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)(5-10 mol %) in DMF. The reaction mixture was then heated (60° C.) forbetween 5 and 75 minutes. The reaction mixture was allowed to cool toambient temperature and was then partitioned between ethyl acetate andbrine. The organic layer was separated, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo. The resultant residue wassubjected to purification, by the general methods described below.

Method N: The appropriate boronic acid/boronate ester (1-3 eq.) wassuspended in anhydrous acetonitrile before the appropriate 5-substituted9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), aqueous sodium carbonate solution or potassium fluoridesolution, and 1,1′-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II) (5-10 mol %) were added and the reaction mixture was thenheated with microwave irradiation (100-160° C.) for between 1 and 30minutes. The resultant residue was purified by one of the generalpurification methods described below. (Deviation: ² Dioxane was used asa solvent instead of acetonitrile).

General Stille Coupling Methods

Method A: The appropriate stannane (1-3 eq.) was suspended in anhydrousdioxane before 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrileor3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) and tetrakis(triphenylphosphine)palladium(0) (5-10 mol %) wereadded and the reaction mixture was then irradiated in the microwave(100-160° C.) for between 15 and 75 minutes. The resultant mixture waspurified by one of the general purification methods described below.

Method B: The appropriate stannane (1-3 eq.) was suspended in anhydrousdioxane before 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrileor3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) and tetrakis(triphenylphosphine)palladium(0) (5-10 mol %) andlithium chloride (1-3 eq.) were added and the reaction mixture was thenirradiated in the microwave (100-160° C.) for between 15 and 30 minutes.The resultant mixture was purified by one of the general purificationmethods described below.

Method C: The appropriate stannane (1-3 eq.) was suspended in anhydrousdioxane before the appropriate 5-substituted9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), tetrakis(triphenylphosphine)palladium(0) (5-10 mol %) andcopper thiophene carboxylate (5-30 mol %) were added and the reactionmixture was then heated with microwave irradiation (100-160° C.) forbetween 1 and 30 minutes. The resultant residue was purified by one ofthe general purification methods described below.

General Sonagashira Coupling Methods

Method A: The appropriate acetylene (1.0 eq.) was added to a solution of3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1.0 eq.), tetrakis(triphenylphosphine)palladium(0) (10 mol %), andcopper (I) iodide (25 mol %) in anhydrous DMF, under nitrogen. Thereaction mixture was irradiated in the microwave (100° C.) for 10minutes. The resulatant mixture was concentrated in vacuo and theresultant residue was purified by one of the general purificationmethods described below.

General Ullmann Coupling Methods

Method A: The appropriate phenol (1.5 eq.) was added to a suspension of3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), N,N-dimethylglycine (50 mol %), copper (I) iodide (12.5 mol %),and cesium carbonate (2.0 eq.) in anhydrous dioxane, under argon. Thereaction mixture was then heated (100-120° C.) in a sealed tube forbetween 1 and 3 days. The mixture was concentrated in vacuo and theresultant residue was purified by one of the general purificationmethods described below.

Method B: The appropriate aryl bromide (1-2 eq.) was added to asuspension of3-hydroxy-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), N,N-dimethylglycine (50 mol %), copper (I) iodide (15 mol %),and cesium carbonate (2.0 eq.) in anhydrous dioxane, under argon. Thereaction mixture was then heated under microwave irradiation (150° C.)for between 1 and 2 hours. The mixture was concentrated in vacuo and theresultant residue was purified by one of the general purificationmethods described below.

General Buchwald Coupling Method

Method A: The appropriate amine (1-2 eq.) was added to a suspension of3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) and copper (II) acetate (5 mol %) in methanol, under argon. Thereaction mixture was then heated under microwave irradiation (85-130°C.) for 1-30 minutes. The mixture was concentrated in vacuo and theresultant residue was purified by one of the general purificationmethods described below.

General Mitsunobu Method

Method A: A solution of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), the appropriate hydroxypiperidine carboxylic acid tert-butylester (5 eq.) and triphenylphosphine (5 eq.) in anhydrous DMF oranhydrous THF was treated dropwise with diethyl azodicarboxylate (5 eq.)and the mixture stirred at a temperature between ambient and 50° C. forbetween 2 and 65 hours. The resultant reaction mixture was diluted withethyl acetate and washed with brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The resultant residue was subjectedto purification, by the general methods described below.

Method B:3-Hydroxy-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.), the appropriate hydroxyamine (2-4 eq.) and triphenylphosphine(2-4 eq.) in THF was treated dropwise with diethyl azodicarboxylate (2-4eq.) and the mixture stirred at a temperature between ambient and 50° C.for between 2 and 65 hours. The resultant reaction mixture was dilutedwith DCM and washed with brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The resultant residue was subjected topurification, by the general methods described below.

General Bromide Displacement Methods

Method A:9-Benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) was heated in the appropriate amine (5 eq.) at 160° C. until thereaction deemed complete. The reaction mixture was cooled then dilutedwith water and extracted with an appropriate solvent. The resultantresidue was purified by one of the general purification methodsdescribed below.

Method B:9-Benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) was heated with the appropriate amine (2-3 eq.) andtriethylamine (10-12 eq.) in 1-methyl-2-pyrrolidinone (3 mL) undermicrowave irradiation or thermally in a sealed tube at 160-180° C. untilthe reaction was deemed complete. The reaction mixture was allowed tocool then evaporated. The resultant residue was purified by one of thegeneral purification methods described below.

Method C:9-Benzenesulfonyl-3,5-dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) or 3,5-dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) was heated in the appropriate amine (5 eq.) at 160° C. until thereaction deemed complete. The reaction mixture was cooled then dilutedwith water and extracted with an appropriate solvent. The resultantresidue was purified by one of the general purification methodsdescribed below.

Method D:9-Benzenesulfonyl-3,5-dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) or 3,5-dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) was heated with the appropriate amine (2-3 eq.) andtriethylamine (10-12 eq.) in 1-methyl-2-pyrrolidinone (3 mL) undermicrowave irradiation or thermally in a sealed tube at 160-180° C. untilthe reaction was deemed complete. The reaction mixture was allowed tocool then evaporated. The resultant residue was purified by one of thegeneral purification methods described below.

Method E:9-Benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) was treated with the appropriate amine (10-50 eq.) intetrahydrofuran (3 mL) and then the reaction mixture was stirred atambient temperature until the reaction was deemed complete. The reactionmixture was allowed to cool then evaporated. The resultant residue waspurified by one of the general purification methods described below.

General Reduction Methods

Method A: A solution of the appropriately 5-substituted9-benzenesulfonyl-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrileor 5-substituted3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1.eq) in amixture of DMF and ethyl acetate (1:1 v/v) was treated with Pd/C (10%w/w) and triethylamine (1-5 eq.) then placed under an atmosphere ofhydrogen and the reaction mixture was stirred at ambient temperatureuntil the reaction was deemed complete. The reaction mixture was purgedwith argon then the Pd/C was removed by filtration then the filtrateevaporated. The resultant residue was purified by one of the generalpurification methods described below:

Method B: A solution of the appropriately 5-substituted9-benzenesulfonyl-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrileor 5-substituted3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1.eq) in amixture of ethanol and tetrahydrofuran (1:1 v/v) was treated with Pd/C(10% w/w) then placed under an atmosphere of hydrogen and the reactionmixutre was stirred at ambient temperature until the reaction was deemedcomplete. The reaction mixture was purged with argon then the Pd/C wasremoved by filtration then the filtrate evaporated. The resultantresidue was purified by one of the general purification methodsdescribed below.

General Alkylation Methods

Method A: A solution of the9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq), cesium carbonate (1-5 eq.), sodium iodide (0.5-2 eq.) and1,3-dibromopropane in DMF was heated under microwave irradiation(85-150° C.) for between 1 and 30 minutes until the reaction was deemedcomplete. The reaction mixture was then concentrated in vacuo andsubjected to purification by one of the general methods described below.

Method B: A solution of the9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq), cesium carbonate (1-5 eq.), sodium iodide (0.5-2 eq.) and1,2-dibromoethane in DMF was heated under microwave irradiation (85-150°C.) for between 1 and 30 minutes until the reaction was deemed complete.The reaction mixture was then concentrated in vacuo and subjected topurification by one of the general methods described below.

Method C: To a solution of the appropriate amine (2 eq.) intetrahydrofuran was added sodium hydride (60% dispersion in mineral oil,2-4 eq.). The reaction mixture was stirred at ambient temperature for 5minutes, then a mixture of 4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile with4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1 eq.) was added in one portion and the reaction mixture was stirred atthis temperature for 10 minutes before being warmed to 40° C. for 5 h.The mixture was diluted with water and ethyl acetate then the organiclayer was separated, dried over anhydrous sodium sulfate, filtered,concentrated in vacuo, and purified using one of the general methodsdescribed below.

General Deprotection Methods

Method A: 6N HCl (aqueous solution or in dioxane) was added to a mixtureof the protected substrate in an appropriate solvent and the reactionmixture was stirred between ambient temperature and 75° C., until thereaction was deemed complete. The reaction mixture was concentrated invacuo and subjected to purification by one of the general methodsdescribed below.

Method B: TFA was added to a mixture of the protected substrate in anappropriate solvent at ambient temperature. The mixture was stirreduntil the reaction was deemed complete. The reaction mixture wasconcentrated in vacuo and subjected to purification by one of thegeneral methods described below.

Method C: The tertiary amine was dissolved or suspended in DCM andtreated with an excess (at least 2 equivalents) of 1-chloroethylchloroformate. DIPEA (at least 1 equivalent) was added and the resultantmixture was heated under reflux. When analysis by LCMS showed thatstarting material (or any 1-chloroethyl carbamate of starting material)had been consumed the solution was cooled and concentrated in vacuo. Theresidue was taken up in methanol and heated at reflux until analysis byLCMS showed complete consumption of the intermediates. The reactionmixture was then cooled and concentrated in vacuo. The residue wassubjected to purification by one of the general methods described below.

Method D: IN TBAF in THF was added to a mixture of the protectedsubstrate in an appropriate solvent. The reaction mixture was stirredbetween ambient temperature and 55° C. until the reaction was deemedcomplete. The resultant solution was concentrated in vacuo beforesubjecting the crude material to purification by one of the generalmethods described below. Alternatively, the crude material waspartitioned between water and ethyl acetate and the organic layer wasdried, concentrated in vacuo, before subjecting the crude material toone of the general purification methods described below.

Method E: 2N ammonia in methanol was added to a mixture of the protectedsubstrate. The reaction mixture was stirred at ambient temperature untilthe reaction was deemed complete. The resultant solution wasconcentrated in vacuo before subjecting the crude material topurification by one of the general methods described below.Alternatively, the crude material was partitioned between water andethyl acetate and the organic layer was dried, concentrated in vacuo,before subjecting the crude material to one of the general purificationmethods described below.

Method F: 48% aqueous hydrobromic acid was added to a mixture of theprotected substrate. The reaction mixture was stirred at 75° C. untilthe reaction was deemed complete. The cooled reaction mixture wasbasified to pH 12 with 6N sodium hydroxide solution and then adjusted topH 7-9 with dropwise addition of 1N aqueous hydrochloric acid then theresultant solid was collected by filtration and purified using one ofthe general methods described below.

General Purification Methods

Method A: Si-SPE or Si-ISCO, ethyl acetate/DCM gradient.

Method B: Si-SPE or Si-ISCO or manual silica column, methanol/DCMgradient.

Method C: A solution of the substrate in methanol was loaded onto anIsolute®SCX-2 cartridge. The cartridge was then washed with methanolbefore the desired product was eluted using 2N ammonia in MeOH.

Method D: Reverse phase HPLC Phenomenex Gemini C18, 20 mM triethylaminein water/acetonitrile gradient.

Method E: Si-SPE or Si-ISCO, 2N ammonia in methanol/DCM gradient.

Method F: Ethyl acetate/methanol recrystallisation.

Method G: Solid filtered from reaction mixture and resultant solidwashed thoroughly with water.

Method H: Reaction mixture was diluted with water, filtered and theresulting solid washed with THF.

Method I: Reverse phase HPLC Phenomenex Gemini C 18, 0.1% formic acid inwater/0.1% formic acid in acetonitrile gradient.

Method J: Si-SPE or Si-ISCO, isopropanol/DCM gradient.

Method K: Solid isolated from reaction mixture and washed with ethanol.

Method L: Si-SPE or Si-ISCO, cyclohexane/ethyl acetate gradient.

Method M: C18-ISCO, 10-100% methanol/water gradient

Method N: Redisep Basic Alumina-ISCO, ethyl acetate/cyclohexane gradient

Method 0: Redisep, Basic Alumina-ISCO, methanol/DCM gradient

Method P: Biotage, Snap KP-NH, Amino Silica-ISCO, ethylacetate/cyclohexane gradient

Method Q: Biotage, Snap KP-NH, Amino Silica-ISCO, methanol/DCM gradient

Method R: Si-SPE or Si-ISCO or Biotage Snap-Si, THF/pentane gradientMethod S: Reverse phase HPLC Phenomenex Gemini C 18, water/methanolgradient

Method R: Solid isolated from reaction mixture and triturated with anappropriate solvent.

Method S: Solid isolated from reaction mixture and washed with methanoland diethyl ether.

Method T: Reverse phase HPLC Phenomenex Gemini C18, 0.1% ammoniumhydroxide in water/methanol gradient.

Deviations from Purification General Methods:

¹ Triturated in hot methanol; ² triturated in ethyl acetate; ³triturated in acetonitrile; ⁴ recrystallised from DMSO-water; ⁵triturated in diethyl ether; ⁶ triturated in DCM; ⁷ recrystallised fromacetonitrile; ⁸ recrystallised from ethyl acetate; ⁹ recrystallised frommethanol.

SYNTHESIS OF INTERMEDIATES Preparation of3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1: 3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acidmethyl ester

Bromine (6.76 ml, 132.0 mmol) was added to a mixture of9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (10.0g, 44.0 mmol) and sodium acetate (11.2 g, 136.4 mmol) in acetic acid(360 mL) and then the reaction mixture was heated at 100° C. for 90minutes. The reaction mixture was then cooled to ambient temperature andthe solvent removed under reduced pressure then the residue was treatedwith saturated sodium thiosulfate solution (40 mL) followed by water(100 mL) and then the pH of the aqueous solution was adjusted to 7 bythe addition of saturated sodium hydrogen carbonate solution. Theresultant precipitate was collected by filtration and the solid waswashed with water (20 mL) then dried at 60° C. until constant weight wasachieved, to afford the desired material as an off-white solid (14.0 g,quantitative yield). ¹H NMR (DMSO-D₆, 300 MHz): 9.13 (d, J=2.3 Hz, 1H),9.00 (d, J=2.0 Hz, 2H), 8.70 (d, J=2.3 Hz, 1H), 3.92 (s, 3H). LCMS(Method B): R_(T)=2.92 min, M+H⁺=306/308.

Step 2: 3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acidamide

In a steel bomb, a saturated solution of ammonia in methanol wasprepared by passing gaseous ammonia through methanol (250 mL) then3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester(14.0 g, 38.3 mol) was added. The vessel was sealed, then the reactionmixture was heated at 140° C. (15 bar) for 18 h. After this time, thereaction vessel was allowed to cool to ambient temperature then thereaction mixture was transferred to a round-bottomed flask and thesolvent was removed in vacuo to afford a solid residue. The resultantsolid residue was collected by filtration, washed with methanol (50 mL)and then dried to yield the desired product as a grey solid (9.47 g,85%). ¹H NMR (DMSO-D₆, 400 MHz): 11.53 (s, 1H), 9.14 (d, J=2.3 Hz, 1H),8.96 (d, J=1.1 Hz, 1H), 8.91 (d, J=1.1 Hz, 1H), 8.71 (d, J=2.3 Hz, 1H),8.07 (s, 1H), 7.52 (s, 1H). LCMS (Method B): R_(T)=2.49 min,M+H⁺=291/293.

Step 3: 3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

To a cooled solution (0° C.) of a mixture of3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid amide (5.0g, 17.2 mmol) and triethylamine (24.0 mL, 172 mmol) in THF (200 mL) wasslowly added trifluoroacetic anhydride (12.0 mL, 86 mmol). Upon completeaddition, the reaction mixture was allowed to warm to ambienttemperature and the stirring was continued for an additional 4 h. Afterthis time, the solvent was removed in vacuo and the resultant residuewas loaded onto H-MN. The residue was then purified by flashchromatography (silica, 330 g column, ISCO, 0-100% ethyl acetate inhexane) to afford the title compound as a pale brown solid (2.30 g,49%). ¹H NMR (DMSO-D₆, 300 MHz): 13.05 (s, 1H), 9.08-9.04 (m, 2H), 8.91(d, J=1.1 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H). LCMS (Method B): R_(T)=2.98min, M+H+=271, 273.

Preparation of3-Bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile

To a suspension of3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (300 mg, 1.1mmol) in DMF (2.5 mL), under an inert atmosphere, was added sodiumhydride (65 mg, 1.3 mmol) and the reaction mixture was allowed to stirat ambient temperature for 30 minutes. The reaction mixture was cooledto 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride (0.25 mL, 1.3 mmol)was added dropwise and then the resultant suspension was allowed to warmto room temperature. Water (0.5 mL) was added to the resultantsuspension to quench the reaction, the solvent was removed in vacuo andthe resultant residue was purified by flash chromatography (silica, 12 gcolumn, ISCO, 0-15% ethyl acetate in cyclohexane) to afford the titlecompound as an off-white crystalline solid (266 mg, 62%). ¹H NMR (CDCl₃,400 MHz): 9.18 (d, J=1.2 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.3Hz, 1H), 8.34 (d, J=1.2 Hz, 1H), 5.98 (s, 1H), 3.56-3.60 (m, 2H),0.94-0.98 (m, 2H), 0.08 (s, 9H). LCMS (Method B): R_(T)=4.55 min,M+H⁺=(403, 405).

Preparation of3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1.41 g, 3.5 mmol), bis(pinacolato)diboron (980 mg, 3.85 mmol),potassium acetate (1.0 g, 10.5 mmol) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg,0.175 mmol) in dioxane (18 mL) and DMSO (2 mL) was heated at 120° C., ina sealed vial and under argon, for 18 h. The reaction mixture wasallowed to cool to ambient temperature then quenched by the addition ofsaturated aqueous sodium bicarbonate solution (200 mL) and extractedinto ethyl acetate (200 mL). The organic layer was dried over sodiumsulfate, filtered and evaporated in vacuo and the resultant residue waspurified by flash chromatography (silica, 80 g column, ISCO, 0-50% ethylacetate in cyclohexane) to afford the title compound as a whitecrystalline solid (1.32 g, 84%). ¹H NMR (CDCl₃, 300 MHz): 9.16 (d, J=1.0Hz, 1H), 9.05 (d, J=1.6 Hz, 1H), 8.86 (d, J=1.6 Hz, 1H), 8.37 (d, J=1.0Hz, 1H), 6.03 (s, 2H), 3.61-3.54 (m, 2H), 1.41 (s, 12H), 0.94-0.87 (m,2H), −0.10 (s, 9H). LCMS (Method B): R_(T)=5.0 min, M+H⁺=451.

Preparation of6-Cyano-3-(4-methanesulfonyloxymethylphenyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylicacid tert-butylester

Step 1:6-Cyano-3-(4-hydroxymethylphenyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylicacid ten-butyl ester

A mixture of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1.00 g, 3.70 mmol), 4-bromomethylbenzeneboronic acid (1.18 g, 5.50mmol) and 1,1′-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II)(152 mg, 0.19 mmol) in acetonitrile (40 mL) and 2N aqueous potassiumfluoride solution (20 mL) was devided equally across four 25 mLmicrowave vials. Each vial was degassed with nitrogen for 10 minutesbefore the reaction mixtures were heated under microwave irradiation at175° C. for 90 minutes. The reaction mixtures were then allowed to coolto ambient temperature, combined, diluted with water (100 mL), theresultant solid collected by filtration, washed with water (50 mL) anddiethyl ether (40 mL) and left to air dry. The resultant grey solid wassuspended in acetonitrile (250 mL), di-tert-butyldicarbonate (2.00 g,9.17 mmol) was added and the resulting reaction mixture stirred at 50°C. for 1.5 h. The mixture was allowed to cool to ambient temperature,filtered to remove the solid and the filtrate was evaporated in vacuo.The resultant residue was purified by flash column chromatography(silica, 80 g column, ISCO, 0-70% ethyl acetate in DCM) to afford thetitle compound as a white solid (385 mg, 26%). ¹H NMR (CDCl₃, 400 MHz):9.67 (d, J=1.0 Hz, 1H), 9.08 (d, J=2.3 Hz, 1H), 8.56 (d, J=2.3 Hz, 1H),8.38 (d, J=1.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H),4.81 (d, J=5.9 Hz, 2H), 1.82 (s, 9H), 1.75 (t, J=5.9 Hz, 1H). LCMS(Method B): R_(T)=2.70 min, M(—C₅H₉O₂)+H⁺=301.

Step 2:6-Cyano-3-(4-methanesulfonyloxymethyl-phenyl)-dipyrido[2,3-b:4′,3′-d]pyrrole-9-carboxylicacid tert-butylester

Methanesulfonyl chloride (60 μL, 0.70 mmol) was added to a solution of6-cyano-3-(4-hydroxymethyl-phenyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylicacid tert-butyl ester (224 mg, 0.60 mmol) and triethylamine (110 μL,0.80 mmol) in DCM (20 mL). The mixture was allowed to warm to ambienttemperature and stirred for 2 h. The mixture was diluted with DCM (200mL) and washed with water (100 mL). The organic phase was separated,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo toafford the title compound as yellow oil (374 mg, 99%).

Preparation of Methanesulfonic acid 4-[6-cyano-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl]-benzyl ester

Step 1:(4-Hydroxymethyl-phenyl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(700 mg, 0.87 mmol), 4-hydroxymethylbenzeneboronic acid (400 mg, 1.32mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)(52.5 mg, 0.064 mmol) in acetonitrile (21 mL) and 2N aqueous potassiumfluoride solution (21 mL) was devided equally across two 25 mL microwavevials. Each vial was degassed with nitrogen for 10 minutes before themixtures were heated under microwave irradiation at 140° C. for 30minutes. The reaction mixtures were allowed to cool to ambienttemperature, combined and diluted with water (50 mL). The precipitatewas collected by filtration, washed with water (50 mL) and left to airdry. The resultant grey solid was purified by flash columnchromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate incyclohexane). The isolated solid was then triturated with hot t-BME toafford the title compound as a light grey solid (646 mg, 26%). LCMS(Method B): R_(T)=4.11 min, M+H⁺=431.

Step 2: Methanesulfonic acid4-[6-cyano-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl]-benzylester

Methane sulfonyl chloride (366 mg, 0.25 ml, 3.20 mmol) was added to asuspension of(4-hydroxymethyl-phenyl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(646 mg, 1.56 mmol) and Silicycles' polymer supported diethylamine (2.5g, 3.30 mmol) in acetonitrile (25 mL). The mixture was stirred atambient temperature for 1 h. The resin was removed by filtration, washedwith acetonitrile (50 mL) and the filtrate evaporated in vacuo to afforda pale yellow solid (737 mg, 96%). ¹H NMR (CH₃CN-D₃, 400 MHz): 9.30 (d,J=1.1 Hz, 1H), 9.12 (d, J=2.2 Hz, 1H), 8.98 (d, J=2.2 Hz, 1H), 8.75 (d,J=1.1 Hz, 1H), 7.89-7.85 (m, 2H), 7.65-7.63 (m, 2H), 6.14 (s, 2H), 4.79(s, 2H), 3.92 (s, 3H), 3.75 (t, J=8.1 Hz, 2H), 1.01 (t, J=8.1 Hz, 2H),0.00 (s, 9H).

Step 3:3-Hydroxy-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

To a solution of3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(245 mg, 0.54 mmol) in THF (2.0 mL), under an inert atmosphere, wasadded N-methylmorpholine-N-oxide (191 mg, 1.63 mmol) and the reactionmixture was heated under reflux for 90 minutes. The reaction mixture wasallowed to cool to ambient temperature and the solvent removed in vacuo.The residue was purified by flash chromatography (silica, 12 g column,ISCO 0-50% ethyl acetate in cyclohexane) to afford the title compound asa white solid (180 mg, 97%). ¹H NMR (CD₃OD, 300 MHz): 9.10 (d, J=1.0 Hz,1H), 8.64 (d, J=1.3 Hz, 1H), 8.35 (d, J=2.7 Hz, 1H), 8.04 (d, J=2.7 Hz,1H), 5.99 (s, 2H), 3.59 (t, J=8.0 Hz, 2H), 0.86 (t, J=8.0 Hz, 2H), −0.14(s, 9H). LCMS (Method B): R_(T)=3.75 min, M+H⁺=341.

Preparation of3-tert-Butyl-carbonylamino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of3-bromo-9-(2-trimethylsilanylethoxymethyl)dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1.53 g, 3.79 mmol), tert-butyl carbamate (888 mg, 7.58 mmol), andcesium carbonate (2.47 g, 7.58 mmol) were suspended in 1,4-dioxane (30mL) degassed and purged with nitrogen three times.4,5-bis(Diphenylphosphino)-9,9-dimethylxanthene (219 mg, 0.379 mmol) andtris(dibenzylideneacetone)dipalladium(0) (173 mg, 0.189 mmol) were addedand the reaction mixture heated at 90° C. for 25 h. The cooled reactionmixture was pre-absorbed onto silica gel and purified by flashchromatography on silica (silica, 120 g column, Biotage, 10-60% EtOAc inheptane) to afford the title compound as a white-yellow solid (1.3 g,80%). ¹H NMR (400 MHz, DMSO-D₆): 9.74 (s, 1H), 9.26 (s, 1H), 9.02 (s,1H), 8.95 (s, 1H), 8.67 (d, J=2.4, 1H), 5.98 (s, 2H), 3.55 (t, J=7.9,2H), 1.52 (s, 9H), 0.81 (t, J=7.9, 2H), −0.12-−0.23 (m, 9H).

Preparation of3-Amino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

3-tert-Butyl-carbonylamino-9-(2-trimethylsilanylethoxymethyl)dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(505 mg, 1.15 mmol) in DCM (30 mL) was treated with TFA (0.78 mL) andallowed to stir for 2.5 days at ambient temperature. The reactionmixture was treated with saturated sodium bicarbonate and diluted withDCM and water. The layers were separated, the aqueous phase wasextracted further with DCM, and the combined organic phase was driedover sodium sulfate, filtered and concentrated in vacuo. The resultantresidue was dissolved in ethyl acetate and pre-absorbed onto silica geland purified by flash chromatography (silica, 24 g column, Biotage,1-100% EtOAc in heptane) to afford the title compound as a yellow solid(152 mg, 39%). LCMS (Method D): R_(T)=2.40 min, M+H⁺=340.

Preparation of3-Chloro-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of3-amino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(45.4 mg, 0.134 mmol) in 2M aqueous sulfuric acid (2.0 mL) and AcOH (1.0mL) was cooled to 0° C. and treated with a solution of sodium nitrite(10.2 mg, 0.147 mmol) in water (0.30 mL). After 20 min, the solution ofthe diazonium salt was added slowly to a cooled (0° C.) solution ofcopper (I) chloride (29.1 mg, 0.294 mmol) in 1M hydrochloric acid (0.60mL). The reaction mixture was allowed to warm to ambient temperaturethen diluted with DCM and water. The layers were separated, the aqueousphase extracted further with DCM, and the combined organic phases weredried over sodium sulfate and concentrated in vacuo. The resultantresidue was dissolved in ethyl acetate and pre-absorbed onto silica geland purified by flash chromatography (silica, 4 g column, Biotage, 1-50%EtOAc in heptane) to afford the title compound as a yellow-orange solid(20 mg, 43%). LCMS (Method D): R_(T)=3.61 min, M+H⁺=359/361.

Preparation of4-Chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:9-(2-Trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile

A mixture of3-bromo-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(5.6 g, 14 mmol), ammonium formate (8.8 g, 139 mmol), and zinc (9.1 g,139 mmol) in tetrahydrofuran (85 mL) was heated at 75° C. for 10 h. Thereaction was allowed to cool, filtered over a pad of celite, and washedwith DCM (200 mL). The filtrate was concentrated in vacuo and thenpurified by flash chromatography (silica, 120 g, ISCO, 5-45% ethylacetate in heptane) to afford the title compound as a white solid (3.6g, 80%). ¹H NMR (CDCl₃, 400 MHz): 9.17 (s, 1H), 8.73 (dd, J=4.8 Hz, 1.5Hz, 1H), 8.46 (dd, J=7.8 Hz, 1.5 Hz, 1H), 8.39 (s, 1H), 7.39 (dd, J=7.8Hz, 4.8 Hz, 1H), 6.01 (s, 2H), 3.60 (t, J=8.0 Hz, 2H), 0.93 (t, J=8.0Hz, 2H), −0.09 (s, 9H).

Step 2:9-(2-Trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-1,7-dioxide

To a suspension of hydrogen peroxide-urea adduct (5.9 g, 62.2 mmol) inchloroform (40 mL) was added trifluoroacetic anhydride (8.7 mL, 61.6mmol) dropwise over 10 minutes. The reaction mixture was stirred at roomtemperature for 5 minutes and then to this was added9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(2.0 g, 6.0 mmol) as a solution in chloroform (30 mL). Note: an exothermis observed upon addition of the substrate. The reaction mixture wasstirred at room temperature for 10 minutes and then at 50° C. for 30minutes. The reaction mixture was cooled to room temperature, treatedwith saturated sodium thiosulfate solution (20 mL), and diluted withwater (50 mL) and methanol (10 mL). The layers were separated and theorganic layer was washed with 0.5N hydrochloric acid (50 mL), dried oversodium sulfate, filtered, concentrated in vacuo, and purified by flashchromatography (silica, 80 g, ISCO, 0-10% methanol in dichloromethane)to afford the title compound as a pale yellow solid (930 mg, 40%). ¹HNMR (CDCl₃, 400 MHz): 8.86 (s, 1H), 8.39 (d, J=6.4 Hz, 1H), 8.27 (s,1H), 7.94 (d, J=8.1 Hz, 1H), 7.32 (dd, J=7.9 Hz, 6.5 Hz, 1H), 6.55 (s,2H), 3.73 (t, J=8.0, 2H), 0.93 (t, J=8.0, 2H), −0.04 (s, 9H).

Step 3:4-Chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrid[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxide

A mixture of9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-1,7-dioxide(2.1 g, 5.9 mmol) in N,N-dimethylformamide (50 mL) was treated withmethanesulfonyl chloride (0.78 mL, 10.0 mmol), and the reaction mixturewas stirred at room temperature for 7 h. The reaction mixture was thendiluted with ethyl acetate (150 mL) and water (200 mL). The layers wereseparated and the organic layer was dried over sodium sulfate, filtered,concentrated in vacuo, and purified by flash chromatography (silica, 40g, ISCO, 5-85% ethyl acetate in heptane) to afford the title compound asa 6.5:1 mixture with2-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxiderespectively as an off-white solid (1.7 g, 77%). The mixture was used inthe next step without any further purification. ¹H NMR (CDCl₃, 400 MHz):8.86 (s, 1H), 8.39 (d, J=6.4 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J=8.1 Hz,1H), 7.32 (dd, J=7.9 Hz, 6.5 Hz, 1H), 6.55 (s, 2H), 3.73 (t, J=8.0 Hz,2H), 0.93 (t, J=8.0 Hz, 2H), −0.04 (s, 9H).

Step 4:4-Chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxidewith2-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile-7-oxide(6.5:1, 220 mg, 0.59 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 0.02 mmol), and triethylamine (0.24 mL,1.8 mmol) in acetonitrile (3.1 mL) was heated under microwaveirradiation at 130° C. for 20 minutes. The cooled reaction mixture wasconcentrated in vacuo and purified by flash chromatography (silica, 40g, ISCO, 5-85% ethyl acetate in heptane) to afford the title compound asa 6.5:1 mixture of the title compound with2-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrileas an off-white solid (180 mg, 80%). The mixture was used in subsequentsteps without any further purification. ¹H NMR (CDCl₃, 400 MHz): 9.20(d, J=0.9 Hz, 1H), 8.74 (d, J=0.9 Hz, 1H), 8.60 (d, J=5.3 Hz, 1H), 7.39(d, J=5.3 Hz, 1H), 6.02 (s, 2H), 3.60 (t, J=8.0 Hz, 2H), 0.94 (t, J=8.0Hz, 2H), −0.08 (s, 9H).

2-Chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

The title compound was prepared following the procedure from theprevious step. ¹H NMR (CDCl₃, 400 MHz): 9.17 (s, 1H), 8.38 (d, J=8.2 Hz,1H), 8.35 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 5.97 (s, 2H), 3.61 (t, J=8.0Hz, 2H), 0.95 (t, J=8.0 Hz, 2H), −0.07 (s, 9H).

Preparation of9-Benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:1-Benzenesulfonyl-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester

To 1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester (0.27 g, 0.88 mmol) in 1,2-dichloroethane (5.0 mL) wasadded NBS (0.178 g, 1.00 mmol) and AIBN (0.032 g, 0.20 mmol and thereaction mixture was heated under reflux for 1 h. After cooling toambient temperature the solvent was removed by evaporation and theresultant residue was purified by flash chromatography (silica, 5 gcolumn, ISCO, 0-65% DCM in pentane) to afford the title compound as awhite solid (0.26 g, 72%). LCMS (Method B): R_(T)=3.95 min,M+H⁺=409/411.

Step 2:1-Benzenesulfonyl-2-{[cyanomethyl-(toluene-4-sulfonyl)amino]-methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester

To a cooled (0° C.) mixture of1-benzenesulfonyl-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester (1.64 g, 4.00 mmol) andN-cyanomethyl-4-methyl-benzenesulfonamide (0.93 g, 4.40 mmol) in dry THF(10 mL) was added sodium hydride (0.176 g, 60% dispersion in mineraloil, 4.40 mmol) in two equal portions. The reaction mixture was stirredat 0° C. for 15 minutes then allowed to warm to room temperature. After66 h the reaction mixture was diluted with DCM (60 mL) and saturatedaqueous sodium carbonate solution (25 mL). The layers were separated andthe aqueous phase was extracted with DCM (2×25 mL). The combined organicphase was dried over anhydrous magnesium sulfate and concentrated invacuo. The residue was triturated with THF (5 mL) and the resultantsolid dried in vacuo to afford the title compound as a beige solid (1.72g, 80%). LCMS (Method B): R_(T)=3.91 min, M+H⁺=539.

Step 3:9-Benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Lithium bis(trimethylsilyl)amide (9.6 mL, 1N solution in THF, 9.60 mmol)was added dropwise to a cooled (−78° C.) suspension of1-benzenesulfonyl-2-{[cyanomethyl(toluene-4-sulfonyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester (1.72 g, 3.19 mmol) in dry THF (50 mL). The reactionmixture was allowed to warm to −30° C., stirred at −30° C. for 2 h,before warming to ambient temperature. The reaction mixture was quenchedwith saturated aqueous ammonium chloride solution (30 mL) and water (50mL). The aqueous phase was extracted with DCM (2×20 mL) and the combinedorganic phase was washed with brine and concentrated in vacuo. Theresultant solid was triturated with THF (2×4 mL) to afford the titlecompound. The filtrate was purified by flash chromatography (silica, 5 gcolumn, Si-SPE, ethyl acetate then 10-20% MeOH in DCM) to afford theremaining title compound. The two batches of material were combined toafford a yellow solid (1.03 g, 90%). LCMS (Method B): R_(T)=3.26 min,M+H⁺=351.

Preparation of9-Benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1: 1-Benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester

A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methylester (15.0 mmol), benzenesulfonyl chloride (11.9 g, 8.61 mL, 67.5 mmol)and triethylamine (9.61 g, 13.2 mmol) in dry THF (100 mL) was heatedunder reflux for 19 h. The resultant suspension was allowed to cool toambient temperature and diluted with saturated aqueous sodium carbonatesolution (50 mL) and extracted with DCM (2×50 mL) and THF (1×50 mL). Thecombined organic phase was dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resultant residue was purified by flashchromatography (silica, 50 g cartridge, Si-SPE, 0-100% DCM in pentane).The relevant fractions were concentrated in vacuo and the residue wastriturated with pentane (10 mL) to afford the title compound as a whitesolid (5.25 g, 88%). LCMS (Method B): R_(T)=4.11 min, M+H⁺=395/397.

Step 2:1-Benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester

A solution of1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester (1.58 g, 4.0 mmol) in dry THF (14.0 mL) was addeddropwise to a cold (−78° C.) solution of LDA [freshly prepared fromdiisopropylamine (0.67 mL, 4.8 mmol) and 2.5N n-butyllithium (1.92 mL,4.8 mmol in hexanes) in THF (14 mL)]. The reaction mixture was stirredat −78° C. for 45 minutes before the addition of iodomethane (0.30 mL,4.72 mmol), then the reaction mixture was warmed to 10° C. over 3.5 h. Asolution of sodium dihydrogen phosphate (25 mL) was then added and theresultant mixture was allowed to warm to ambient temperature and thephases were separated. The aqueous phase was extracted with DCM (2×15mL) and the combined organic phase was washed with brine, dried overanhydrous magnesium sulfate and concentrated in vacuo. The resultantresidue was purified by chromatography (silica, 10 g cartridge, Si-SPE,DCM then ethyl acetate) and trituration with pentane to afford the titlecompound (0.42 g, 25%). ¹H NMR (400 MHz, CDCl₃): 8.43 (d, J=2.3 Hz, 1H),8.40 (d, J=2.3 Hz, 1H), 8.20-8.16 (m, 2H), 7.65-7.59 (m, 1H), 7.54-7.49(m, 2H), 3.94 (s, 3H), 3.16 (s, 3H).

Step 3:1-Benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester

To a solution of1-benzenesulfonyl-5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester (0.42 g, 1.0 mmol) in 1,2-dichloroethane (9 mL) wereadded NBS (0.20 g, 1.1 mmol) and AIBN (30 mg, 0.2 mmol) and the reactionmixture was heated under reflux for 45 minutes. The reaction mixture wasallowed to cool to ambient temperature and was diluted with pentane (4.0mL), the solid was removed by filtration and the liquors were thenconcentrated in vacuo. The resultant residue was purified bychromatography (silica, 5 g cartridge, Si-SPE, 30-100% DCM in pentane)to afford the title compound as a white solid (0.46 g, 90%). LCMS(Method B): R_(T)=4.55 min, M+H⁺=489.

Step 4:1-Benzenesulfonyl-5-bromo-2-{[cyanomethyl-(toluene-4-sulfonyl)amino]-methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester

Sodium hydride (48 mg, 60% dispersion in mineral oil, 12.0 mmol) wasadded to a cooled (0° C.) mixture of1-benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester (0.56 g, 1.16 mmol) andN-cyanomethyl-4-methyl-benzenesulfonamide (0.25 g, 1.20 mmol) in dry THF(3.5 mL). The reaction mixture was stirred at 0° C. for 15 minutes, thenallowed to warm to ambient temperature and stirred for 18 h. Thereaction mixture was then diluted with DCM (40 mL), saturated aqueoussodium carbonate solution (20 mL) and water (20 mL). The organic phasewas separated, washed with brine, dried over anhydrous magnesium sulfateand concentrated in vacuo. The resultant residue was purified by flashcolumn chromatography (silica, 5 g cartridge, Si-SPE, DCM) to afford thetitle compound as a beige solid (0.59 g, 80%). LCMS (Method B):R_(T)=4.28 min, M+H⁺=617/619.

Step 5:9-Benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Lithium bis(trimethylsilyl)amide (2.34 mL of a 1N solution in THF, 2.34mmol) was added dropwise to a cooled (−78° C.) suspension of1-benzenesulfonyl-5-bromo-2-{[cyanomethyl-(toluene-4-sulfonypamino]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid methyl ester (0.48 g, 0.78 mmol) in dry THF (12 mL). The reactionmixture was allowed to slowly warm to −10° C. and then quenched withsaturated aqueous ammonium chloride solution (8 mL). The reactionmixture was diluted with water and washed with DCM (2×10 mL). Thecombined organic phase was dried over anhydrous magnesium sulfate andconcentrated in vacuo. The resultant residue was purified by flashchromatography (silica, 5 g cartridge, Si-SPE, 10-100% THF in DCM) toafford the title compound as a brown solid (0.20 g, 60%). LCMS (MethodB): R_(T)=3.83 min, M+H⁺=429/431.

Preparation of 1,1,2,2,3,3,4,4,4-Nonafluoro-butane-1-sulfonic acid9-benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylester

Pyridine (23.5 mL, 290 mmol) was added to a suspension of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(5.01 g, 11.7 mmol) in DCM (400 mL) at room temperature. The resultantsolution was cooled to 0° C. then nonafluorobutanesulfonic anhydride(7.16 mL, 23.4 mmol) was added portionwise over 15 minutes maintainingthe internal temperature below 5° C. The reaction mixture was stirredfor 15 minutes at 0° C. then at room temperature for 3 h. The solutionwas cooled to 0° C. and 1M hydrochloric acid (290 mL) was added then themixture was extracted with DCM (×3) and the combined organic phase wasdried over sodium sulfate, filtered and evaporated. The residue wastriturated with DCM and the resultant solid collected by filtration. Thefiltrate was purified by chromatography (silica, 50 g column, DCM) andthe appropriate fractions were combined with the solid collectedpreviously and dried to afford the title compound (6.63 g, 80%). ¹H NMR(CDCl₃, 300 MHz): 9.93 (s, 1H); 8.86 (d, J=2.2 Hz, 1H); 8.75 (d, J=2.2Hz, 1H); 8.30-8.24 (m, 2H); 7.73-7.65 (m, 1H); 7.61-7.52 (m, 2H).

Preparation of9-Benzenesulfonyl-3,5-dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonic acid9-benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylester (6.63 g, 9.3 mmol) and tetra n-butylammonium bromide (11.3 g, 35mmol) in 1,4-dioxane (400 mL) was heated under reflux for 2 h. Thereaction mixture was evaporated to about a third of the original volumethen left to stand overnight. The residue was taken up in DCM andpurified twice by flash chromatography (silica, 70 g column, DCM) toafford the title compound (1.79 g, 39%). ¹H NMR (DMSO-D₆, 300 MHz): 9.73(d, J=0.6 Hz, 1H); 9.10 (d, J=2.3 Hz, 1H); 8.99 (d, J=2.3 Hz, 1H);8.28-8.21 (m, 2H); 7.82-7.74 (m, 1H); 7.68-7.57 (m, 2H).

Preparation of9-Benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(500 mg, 1.16 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(500 mg, 2.40 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (200 mg, 0.25 mmol) in 2N aqueouspotassium acetate (3.6 mL) and acetonitrile (7.2 mL) was heated undermicrowave irradiation at 140° C., for 30 minutes. The reaction mixturewas allowed to cool to ambient temperature, 1M hydrochloric acid (7.5mL) was added and the mixture was stirred at room temperature for 1 h.The resulting precipitate was collected by filtration, washed withacetonitrile (5 mL) and left to air dry to afford the title compound asa crude brown solid (500 mg, 99%). LCMS (Method G): R_(T)=3.84 min,M+H=431.

Preparation of 1,1,2,2,3,3,4,4,4-Nonafluoro-butane-1-sulfonic acid9-benzenesulfonyl-6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylester

1,1,2,2,3,3,4,4,4-Nonafluorobutanesulfonic anhydride (0.75 g, 0.40 mL,1.3 mmol) was added dropwise to a suspension of9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(106 mg, 0.25 mmol) in pyridine (0.7 mL, 8.0 mmol) and dry DCM (7 mL) at0° C. The reaction mixture was then allowed to warm to ambienttemperature and stirred for 4 h. The reaction mixture was treated with1N hydrochloric acid (6 mL) and the phases were separated. The aqueousphase was extracted with DCM (2×10 mL), the combined organic phase wasdried over anhydrous magnesium sulfate and concentrated in vacuo. Theresultant residue was purified by chromatography (silica, 2 g column,Si-SPE, gradient of DCM/EtOAc) and further trituration with pentane (2mL) to afford the title compound as a white solid (150 mg, 84%). ¹H NMR(CDCl₃, 400 MHz): 9.95 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1Hz, 1H), 8.35-8.32 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.74-7.68 (m, 2H),7.61-7.56 (m, 2H), 4.04 (s, 3H). LCMS (Method G): R_(T)=4.80 min,M+H⁺=713.

Preparation of9-Benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of 1,1,2,2,3,3,4,4-octafluoropentane-1-sulfonic acid9-benzenesulfonyl-6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylester (150 mg, 0.2 mmol) and tetrabutylammonium bromide (240 mg, 0.75mmol) in dry dioxane (10 mL) was heated at reflux for 1 h. The reactionmixture was allowed to cool to ambient temperature and was thenconcentrated in vacuo. The resultant residue was purified bychromatography (silica, 2 g column, Si-SPE, gradient of DCM/EtOAc) andfurther trituration with acetonitrile (2 mL) to afford the titlecompound as a white solid (60 mg, 60%). ¹H NMR (CDCl₃, 400 MHz): 9.84(s, 1H), 8.95-8.92 (m, 2H), 8.27-8.24 (m, 2H), 7.84 (d, J=0.9 Hz, 1H),7.74 (s, 1H), 7.65-7.60 (m, 1H), 7.55-7.49 (m, 2H), 4.01 (s, 3H). LCMS(Method G): R_(T)=4.56 min, M+H⁺=493.

Preparation of9-Benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(102 mg, 0.2 mmol) in acetonitrile (10 mL) was treated with ethyl iodide(34 mg, 17.4 μL, 0.2 mmol). The reaction mixture was heated for 24 h at50° C., until analysis (TLC/LCMS) showed complete consumption ofstarting material. The reaction mixture was allowed to cool to ambienttemperature and was then concentrated in vacuo. The resultant residuewas partitioned between ethyl acetate (10 mL) and 1M sodium carbonatesolution (5 mL). The organic layer was separated, dried over anhydroussodium sulfate, filtered and evaporated in vacuo. The resultant residuewas purified by chromatography (silica, Si-SPE, EtOAc) to afford thetitle compound as a white solid (72 mg, 60%). ¹H NMR (CDCl₃, 400 MHz,):9.56 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.65 (s, 1H), 8.25-8.22 (m, 2H),7.67-7.62 (m, 1H), 7.54-7.49 (m, 2H), 5.15 (s, 1H), 2.96 (s, 2H), 2.48(s, 2H), 2.23 (s, 4H), 2.02 (d, J=16.9 Hz, 2H), 1.18-1.04 (m, 3H). LCMS(Method G): R_(T)=3.5 min, M+H⁺=541.

Preparation of 6-Bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1: 6-Bromo-4-iodo-nicotinic acid

n-Butyllithium (2.5M in hexanes, 297 mL, 0.743 mol) was added over 1 hto a cooled (−25° C.) solution of 2,2,6,6,-tetramethylpiperidine (131mL, 0.77 mol) in tetrahydrofuran (1 L). The mixture was left to stir for16 h at −25° C. then cooled to −55° C. before addition of solid6-bromonicotinic acid (50.0 g, 0.25 mmol). The mixture was allowed towarm to −20° C. and stirred for 2 h. The reaction mixture was cooled to−70° C. then poured onto a pre-cooled (−70° C.) solution of iodine(188.5 g, 0.74 mol) in tetrahydrofuran (500 mL). The mixture was thenpoured into the original reaction vessel and the contents allowed towarm to ambient temperature and stirred for 1 h. The solvent wasevaporated and the resultant residue dissolved in water (500 mL) andwashed with dichloromethane (3×300 mL). The aqueous phase was separatedand the pH adjusted to 2 by the addition of concentrated hydrochloricacid. Aqueous sodium metabisulfite solution (20% w/w, 30 mL) was addedand the solid which deposited was collected by filtration. The resultantsolid was washed with water (75 mL) and pentane (75 mL) and dried at 75°C. under vacuum to furnish the title compound as a tan solid (53.1 g,65%). ¹H NMR (DMSO-D₆, 300 MHz): 8.62 (s, 1H), 8.35 (s, 1H). LCMS(Method B): R_(T)=2.16 min, M+H⁺=328/330.

Step 2: (6-Bromo-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester

A mixture of 6-bromo-4-iodo-nicotinic acid (18.3 g, 55.7 mmol),diphenylphosphorylazide (18 mL, 83.6 mmol) and triethylamine (23.5 mL,167.2 mmol) in tert-butanol (110 mL) and toluene (120 mL) was heated at110° C. for 3 h. The mixture was allowed to cool to ambient temperaturethen evaporated under reduced pressure. The resultant oil was treatedwith water (150 mL) and extracted with ethyl acetate (2×300 mL). Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand evaporated to give a black solid. The resultant black solid wastriturated with methanol (75 mL), collected by filtration, then washedwith diethyl ether (30 mL) and left to air dry to afford the titlecompound as a brown solid (7.5 g, 34%). The remaining filtrate wasevaporated and purified by flash chromatography on a pad of silica. Thepad was washed with 20% ethyl acetate in cyclohexane. Collecting allfractions containing product followed by evaporation in vacuo andtrituation with cyclohexane afforded further title compound (8.9 g, 40%)as a white solid (combined yield—16.4 g, 74%). ¹H NMR (CDCl₃, 300 MHz):8.95 (s, 1H), 7.87 (s, 1H), 6.64 (s, 1H), 1.54 (s, 9H). LCMS (Method B):R_(T)=3.83 min, M+H⁺=399/401.

Step 3: 6-Bromo-4-iodo-pyridin-3-ylamine

(6-Bromo-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (13.6 g,34.1 mmol) was dissolved in dichloromethane (150 mL) and trifluoroaceticacid (50 mL) was then added. The resultant solution was stirred atambient temperature for 2 h then evaporated under reduced pressure. Theresultant residue was treated with a saturated solution of sodiumhydrogen carbonate and the resultant solid was treated with water (50mL) then extracted with ethyl acetate (2×200 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedunder reduced pressure to afford the title compound as an off-whitesolid (10.0 g, 98%). ¹H NMR (CDCl₃, 300 MHz): 7.81 (s, 1H), 7.73 (s,1H), 4.14 (s, 2H). LCMS (Method B): R_(T)=3.03 min, M+H⁺=299/301.

Step 4: 6′-Bromo-2-fluoro-[3,4′]bipyridinyl-3′-ylamine

A mixture of 6-bromo-4-iodo-pyridin-3-ylamine (10.0 g, 33.4 mmol),2-fluoropyridine-3-boronic acid (5.2 g, 36.8 mmol) and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane complex (2.73 g, 3.34 mmol) in acetonitrile (150 mL) and1N aqueous potassium fluoride solution (150 mL) was degassed withnitrogen for 20 minutes. The reaction mixture was heated at 70° C. for2.5 h, allowed to cool to ambient temperature and then partitionedbetween ethyl acetate (400 mL) and water (150 mL). The organic layer wasseparated, dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo. The resultant solid residue was triturated withdichloromethane: methanol (1:1, 100 mL), collected by filtration andwashed with diethyl ether (50 mL) to furnish the title compound as abrown solid (3.5 g, 39%). The filtrate was evaporated and purified bypassing the resultant residue through a pad of silica eluting with ethylacetate:cyclohexane (1:1). Collection of the appropriate fractions andevaporation to dryness afforded a solid that was then triturated withdiethyl ether to afford the title compound as a brown solid (3.7 g, 42%)(combined yield—7.22 g, 81%). ¹H NMR (CDCl₃, 300 MHz): 8.34 (ddd, J=4.9,2.0, 1.2 Hz, 1H), 7.99 (s, 1H), 7.85 (ddd, J=9.4, 7.4, 2.0 Hz, 1H), 7.37(ddd, J=7.4, 4.9, 2.0 Hz, 1H), 7.22 (s, 1H), 3.75 (s, 2H). LCMS (MethodB): R_(T)=2.78 min, M+H⁺=268/270.

Step 5: 6-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of 6′-bromo-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (7.22 g,26.9 mmol) in THF (75 mL) was added dropwise over 10 minutes to sodiumbis-(trimethylsilyl)amide (1N solution in THF, 54 mL, 53.9 mmol). Thereaction mixture was left to stir for 2.5 h then 1N aqueous potassiumfluoride solution (7 mL) was added and the solvent evaporated in vacuo.The residue was diluted with water (100 mL) and the resultant solid wascollected by filtration, washed with water (20 mL) and diethylether:pentane (1:1, 20 mL) and left to air dry. The resultant solid wastriturated with methanol (50 mL), collected by filtration, washed withmethanol (10 mL) and diethyl ether (20 mL) and pentane (20 mL) and leftto air dry to afford the title compound as a brown solid (5.0 g, 75%).¹H NMR (DMSO-D₆, 300 MHz): 8.73-8.69 (m, 2H), 8.63 (dd, J=4.8, 1.7 Hz,1H), 8.48 (dd, J=1.0 Hz, 1H), 7.33 (dd, J=7.8, 4.8 Hz, 1H). LCMS (MethodB): R_(T)=2.43 min, M+H⁺=248/250.

Step 6: 6-Bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of iodine monochloride (32.5 g, 200 mmol) in acetic acid (120mL) was added portionwise over 2 h to a mixture of6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (5.0 g, 20 mmol) and sodiumacetate (18.2 g, 221 mmol) in acetic acid (120 mL) at 100° C. Thereaction mixture was cooled to ambient temperature and poured intosaturated sodium metabisulfite solution (20% w/w, 400 mL). The resultantprecipitate was collected by filtration and the solid was washed withwater (50 mL) and diethyl ether (2×50 mL) then dried at 45° C. untilconstant weight was achieved, to afford the title compound as a greysolid (6.3 g, 83%). ¹H NMR (DMSO-D₆, 300 MHz): 12.49 (s, 1H), 9.14 (d,J=2.1 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.71 (s, 1H), 8.49 (s, 1H). LCMS(Method B): R_(T)=3.40 min, M+H⁺=374/376.

Preparation of 3-Bromo-6-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1: 6-Chloro-4-iodo-pyridin-3-ylamine

(6-Chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (3.67 g,10.3 mmol) was dissolved in DCM (32 mL) and TFA (8 mL) was added. Thereaction mixture was stirred at ambient temperature for 2 h and thenevaporated in vacuo. The resultant residue was treated with 5N aqueoussodium hydroxide solution (25 mL), diluted with water (100 mL) andextracted into ethyl acetate (2×100 mL). The combined organic layer wasdried over anhydrous sodium sulfate, filtered and evaporated in vacuo toafford the title compound as yellow solid (2.37 g, 90%). ¹H NMR (CD₃OD,300 MHz): 7.80 (s, 1H), 7.60 (s, 1H), 4.14 (s, 2H). LCMS (Method B):R_(T)=3.00 min, M+H⁺=255.

Step 2: 5-Bromo-6′-chloro-2-fluoro-[3,4′]bipyridinyl-3′-ylamine

A mixture of 6-chloro-4-iodo-pyridin-3-ylamine (2.37 g, 9.31 mmol),2-fluoro-5-bromopyridine-3-boronic acid (2.64 g, 12.0 mmol) and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.76 g,0.93 mmol) in acetonitrile (35 mL) and 1N aqueous potassium fluoridesolution (35 mL) was degassed with nitrogen for 20 minutes. The reactionmixture was heated at 80° C. for 3 h, allowed to cool to ambienttemperature then partitioned between ethyl acetate (100 mL) and water(75 mL). The organic layer was separated, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo. The resultant solid residuewas triturated using 1:1 DCM/methanol, collected by filtration, washedwith diethyl ether and ethyl acetate to afford the title compound as atan solid (1.37 g, 49%). The filtrate was concentrated under reducedpressure and the resiude was purified by flash chromatography (silica,80 g column, ISCO, 0-40% ethyl acetate in pentane) to afford furthertitle compound as a brown solid (0.73 g, 26%). ¹H NMR (DMSO-D₆, 300MHz): 8.46 (dd, J=2.5, 1.3 Hz, 1H), 8.24 (dd, J=8.3, 2.5 Hz, 1H), 7.88(s, 1H), 7.19 (s, 1H), 5.57 (s, 2H). LCMS (Method B): R_(T)=3.21 min,M+H⁺=304.

Step 3: 3-Bromo-6-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of 5-bromo-6′-chloro-2-fluoro-[3,4′]ipyridinyl-3′-ylamine(2.21 g, 7.32 mmol) in THF (124 mL) was added dropwise over 10 minutesto sodium his-(trimethylsilyl)amide ON solution in THF, 14.6 mL, 14.6mmol). The reaction mixture was stirred for 1 h at ambient temperatureand then quenched by the addition of water (2 mL). The resultant brownsolution was partitioned between ethyl acetate (75 mL) and brine (50mL). An off-white solid precipitated and was collected by filtration toafford the title compound as a grey solid (1.01 g, 49%). ¹H NMR(DMSO-D₆, 300 MHz): 9.01 (d, J=2.3 Hz, 1H), 8.73 (s, 1H), 8.70 (d, J=2.3Hz, 1H), 8.35 (s, 1H). LCMS (Method B): R_(T)=3.33 min, M+H⁺=284.

Preparation of 4-(4-Bromobenzyl)-1-methylpiperidine

A mixture of 4-(4-bromobenzyl)-piperidine (290 mg, 1.14 mmol), formicacid (12 mL) and 37% aqueous formaldehyde (0.30 mL, 3.75 mmol) wasdivided into three portions. Each portion was heated at 150° C. for 5minutes in a microwave reactor. The combined cold mixture was loadedonto a 5 g SCX-2 cartridge which was then washed with methanol (30 mL)then 2 N ammonia in methanol (50 mL). Concentration of the combinedbasic fractions in vacuo gave the title compound (300 mg, 98%) as acolourless oil. LCMS (Method B): R_(T)=2.18 min, M+H⁺=268, 270.

Preparation of 4-(3-Bromo-5-methoxyphenoxy)-1-methylpiperidine

To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0mmol) in DMF (20 mL) at 65° C. was slowly added a solution of4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). Afterstirring for 30 minutes, a solution of 3-bromo-5-fluoroanisole (2.05 g,10 mmol) in DMF (7.0 mL) was added and the reaction mixture was stirredat 65° C. for 24 h. The reaction mixture was allowed to cool to ambienttemperature then was poured into water (200 mL) and extracted with ethylacetate (2×100 mL). The combined organic layers were loaded onto a SCX-2cartridge, which was then washed with acetonitrile then eluted with 2Nammonia in methanol. Concentration of the basic methanolic fractions invacuo gave the title compound (1.5 g, 50%). ¹H NMR (CDCl₃, 400 MHz):6.65 (dd, J=2.2, 1.6 Hz, 1H), 6.63 (dd, J=2.3, 1.6 Hz, 1H), 6.37 (dd,J=2.3, 2.1 Hz, 1H), 4.29-4.21 (m, 1H), 3.75 (s, 3H), 2.70-2.61 (m, 2H),2.31-2.21 (m, 5H), 2.01-1.93 (m, 2H), 1.86-1.75 (m, 2H). LCMS (MethodB): R_(T)=2.1 min, M+H⁺=300.

Preparation of 4-(3,5-Dibromophenoxy)-1-methylpiperidine

To a suspension of sodium hydride (60% in mineral oil, 600 mg, 15.0mmol) in DMF (20 mL), at 65° C., was slowly added a solution of4-hydroxy-1-methylpiperidine (1.15 g, 10 mmol) in DMF (7.0 mL). Afterstirring for 1 h, a solution of 1,3-dibromo-5-fluorobenzene (1.26 mL,10.0 mmol) in DMF (7.0 mL) was added and the reaction mixture wasstirred at 65° C. for 3 days. The mixture was allowed to cool to ambienttemperature then poured into water (100 mL) and extracted with ethylacetate (150 mL). The organic layer was washed with water (100 mL) andloaded onto an SCX-2 cartridge, which was then washed with acetonitrileand eluted with 2N ammonia in methanol. Concentration of the basicmethanolic fraction in vacuo gave the title compound (1.88 g, 54%). ¹HNMR (CDCl₃, 400 MHz): 7.22 (t, J=1.6 Hz, 1H), 6.98 (d, J=1.7 Hz, 2H),4.31-4.23 (m, 1H), 2.69-2.59 (m, 2H), 2.37-2.18 (m, 5H), 2.01-1.92 (m,2H), 1.86-1.75 (m, 2H). LCMS (Method B): R_(T)=2.3 min, M+H⁺=350.

Preparation of 1-(4-Bromo-2,6-difluorobenzyl)-piperidine

Methane sulfonyl chloride (0.38 mL, 4.93 mmol) was added dropwise to acooled (0° C.) solution of (4-bromo-2,6-difluorophenyl)-methanol (1.00g, 4.48 mmol) and triethylamine (0.75 mL, 5.38 mmol) in DCM (50 mL). Thereaction mixture was allowed to warm to ambient temperature and stirredfor 2 h. The mixture was diluted with DCM (30 mL) and washed with water(20 mL). The organic phase was separated, dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to afford a colourless oil.The oil was dissolved in acetonitrile (30 mL), piperidine (0.53 mL, 5.38mmol) and potassium carbonate (0.93 g, 6.72 mmol) were added and thereaction mixture was heated at 50° C. for 90 minutes. The reactionmixture was allowed to cool to ambient temperature and the solid removedby filtration. The filtrate was evaporated in vacuo and the resultantresidue purified by flash column chromatography (silica, 12 g column,ISCO, 0-40% ethyl acetate in cyclohexane) to afford the title compoundas a colourless oil (1.23 g, 99%). ¹H NMR (CDCl₃, 300 MHz): 7.07 (d,J=6.6 Hz, 2H), 3.62 (t, J=1.7 Hz, 2H), 2.41 (t, J=5.1 Hz, 4H), 1.59-1.50(m, 4H), 1.42-1.33 (m, 2H). LCMS (Method B): R_(T)=1.67 min,M+H⁺=290/292.

Preparation of 1-[1-(4-Bromophenyl)-1-methyl-ethyl]-piperidine

In a three necked round bottom flask fitted with a condenser andnitrogen stream, was placed a small quantity of ground glass andmagnesium turnings (190 mg, 7.40 mmol). The mixture was stirred for 30minutes under vacuum then placed under nitrogen and iodine added (onesmall crystal), followed by the rapid addition of 1,4-dibromobenzene(2.43 g, 10.3 mmol) in 15 ml of anhydrous diethyl ether. The reactionmixture was then heated under reflux for 5 minutes. After this time, asolution of 1-(1-cyano-1-methylethyl)-piperidine (1.0 g, 6.60 mmol) inanhydrous THF was added dropwise resulting in the formation of a whiteprecipitate. The reaction mixture was heated under reflux for 1.5 h,before cooling to ambient temperature. The resultant mixture was treatedwith saturated aqueous potassium carbonate solution and extracted withDCM. The organic extract was dried over magnesium sulfate andconcentrated in vacuo. The crude residue was purified by columnchromatography (silica, 12 g column, ISCO, 0-40% ethyl acetate incyclohexane) to afford the title compound (200 mg, 95%) as a colourlessoil. LCMS (Method B): R_(T)=1.99 min, M+H⁺=282, 284.

Preparation of 1-(4-Bromobenzyl)-azetidine

A solution of 4-bromobenzyl bromide (1.00 g, 4.0 mmol) and triethylamine(0.84 ml, 6.0 mmol) in THF (20 mL) was stirred at ambient temperaturefor 10 minutes. Azetidine (0.54 ml, 8.0 mmol) was then added and a whiteprecipitate resulted. The slurry was stirred at ambient temperature for18 h then evaporated in vacuo. The resultant residue was partitionedbetween DCM and saturated aqueous sodium hydrogen carbonate, the organicphase was separated, dried over magnesium sulfate and concentrated invacuo to afford the title compound (0.76 g, 3.40 mmol) as a colourlessoil. ¹H NMR (CDCl₃, 400 MHz): 7.42 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.2 Hz,2H), 3.50 (s, 2H), 3.19 (t, J=7.0 Hz, 4H), 2.08 (p, J=7.0 Hz, 2H).

Preparation of 1-(4-Bromobenzyl)-cis-2,6-dimethylpiperidine

A mixture of 1-bromo-4-bromomethylbenzene (500 mg, 2.0 mmol),cis-2,6-dimethylpiperidine (0.30 mL, 2.2 mmol) and potassium carbonate(332 mg, 2.4 mmol) in acetonitrile (20 mL) was heated under reflux for 2h. The reaction mixture was allowed to cool to ambient temperature, thesolid removed by filtration and the filtrate evaporated in vacuo. Theresultant residue was partitioned between ethyl acetate (100 mL) andwater (25 mL). The organic phase was dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo to give the title compound asa pale brown oil (464 mg, 82%). ¹H NMR (CDCl₃, 300 MHz): 7.40 (d, J=8.3Hz, 2H), 7.27 (d, J=7.0 Hz, 2H), 3.71 (s, 2H), 2.56-2.36 (m, 2H),1.68-1.61 (m, 1H), 1.61-1.47 (m, 2H), 1.33-1.24 (m, 3H), 1.01 (d, J=6.2Hz, 6H). LCMS (Method B): R_(T)=0.8 min, M+H⁺=282/284.

Preparation of 4-(4-Bromophenyl)-4-hydroxypiperidine-1-carboxylic acidtert-butyl ester

Triethylamine (3.69 mL, 26.3 mmol) was added to a solution of4-(4-bromo-phenyl)-piperidin-4-ol (5.18 g, 20.2 mmol) and di-tert-butyldicarbonate (5.30 g, 20.2 mmol) in DCM (60 mL). The resultant reactionmixture was stirred at ambient temperature for 18 h, then diluted withwater (100 mL) and extracted into DCM (3×50 mL). The combined organicphase was concentrated in vacuo and the residue purified by flashchromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate incyclohexane) to afford the title compound as a white solid (7.03 g,98%). ¹H NMR (CDCl₃, 300 MHz): 7.49 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5Hz, 2H), 4.04 (d, J=13.0 Hz, 2H), 3.29-3.15 (m, 2H), 1.96 (td, J=13.0,5.0 Hz, 2H), 1.69 (dd, J=14.0, 2.5 Hz, 2H), 1.48 (s, 9H). LCMS (MethodB): R_(T)=3.88 min.

Preparation of 4-(4-Bromophenyl)-4-methoxypiperidine-1-carboxylic acidtert-butyl ester

Sodium hydride (76 mg, 1.90 mmol) was added portionwise to a solution of4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester(519 mg, 1.46 mmol) in anhydrous THF (10 mL) at 0° C. After 1 h, methyliodide (136 μL, 2.19 mmol) was added and the reaction mixture wasallowed to warm to ambient temperature and stirred for 18 h. Thereaction was quenched by the addition of water (10 mL), the organiclayer was separated and the aqueous layer back-extracted with DCM (3×10mL). The combined organic phase was concentrated in vacuo to afford thetitle compound (607 mg, quantitative). ¹H NMR (CDCl₃, 400 MHz): 7.49 (d,J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 3.97 (d, J=13.0 Hz, 2H), 3.15 (t,J=13.0 Hz, 2H), 2.97 (s, 3H), 1.97 (d, J=13.5 Hz, 2H), 1.83-1.74 (m,2H), 1.47 (s, 9H). LCMS (Method B): R_(T)=4.61 min.

Preparation of 4-(4-Bromophenyl)-4-fluoropiperidine-1-carboxylic acidtert-butyl ester

[Bis(2-Methoxyethyl)amino]sulfur trifluoride (2.1 mL, 11.4 mmol) wasadded to a stirred solution of4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester(810 mg, 2.28 mmol) in anhydrous DCM (25 mL), at −78° C. The reactionmixture was allowed to warm to ambient temperature and stirred for 72 h.The reaction mixture was quenched by the addition of saturated aqueouspotassium carbonate (10 mL) and extracted into DCM (3×10 mL). Thecombined organic phase was concentrated in vacuo and the residuepurified by flash chromatography (silica, 40 g column, ISCO, 0-100%ethyl acetate in cyclohexane) to afford the title compound as acolourless oil (738 mg, 91%). ¹H NMR (CDCl₃, 300 MHz): 7.50 (d, J=8.5Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 4.19-4.05 (m, 2H), 3.29-3.05 (m, 2H),2.04-1.84 (m, 4H), 1.49 (s, 9H). LCMS (Method B): R_(T)=4.55 min.

Preparation of 1-(5-Bromothiophen-3-ylmethyl)-piperidine

Step 1: 5-Bromothiophene-3-carboxylic acid

To a solution of thiophene-3-carboxylic acid (5.00 g, 39.0 mmol) inacetic acid (140 mL), was added dropwise, a solution of bromine (6.60 g,40.0 mmol) in acetic acid (40 mL). The reaction mixture was stirred for30 minutes and then poured into water. The resultant solid was collectedby filtration to afford the title compound as a grey solid (2.07 g,26%). LCMS (Method B): R_(T)=2.9 min, M+H⁺=208.

Step 2: (5-Bromothiophen-3-yl)-piperidin-1-yl-methanone

To a solution of 5-bromothiophene-3-carboxylic acid (1.03 g, 5.00 mmol)in acetonitrile (10 mL), were added HATU (2.09 g, 5.50 mmol), DIPEA (2.6mL, 15.0 mmol) and piperidine (1.0 mL, 10.0 mmol) and the reactionmixture was stirred at room temperature for 24 h. The reaction mixturewas diluted with ethyl acetate (75 mL) and was washed with saturatedaqueous citric acid (2×50 mL). The orgainic layer was concentrated invacuo and the resultant residue was loaded onto an SCX-2 cartridge.Eluting with acetonitrile and evaporation of the organic fraction invacuo afforded the title compound as an off-white solid (1.00 g, 73%).LCMS (Method B): R_(T)=3.3 min, M+H⁺=274.

Step 3: 1-(5-Bromothiophen-3-ylmethyl)-piperidine

To a solution of (5-bromothiophen-3-yl)-piperidin-1-yl-methanone (907mg, 3.30 mmol) in DCM (33 mL) was added tetrabutylammonium borohydride(2.54 g, 9.90 mmol) portionwise over 10 minutes. The reaction mixturewas heated under reflux for 19 h then further tetrabutylammoniumborohydride (2.54 mg, 9.90 mmol) was added to the reaction mixture, infour portions over 6 h. and then the reaction mixture was heated underreflux for 18 h. After this time the reaction mixture was partitionedbetween DCM (100 mL) and saturated aqueous sodium bicarbonate solution(100 mL). The organic layer was dried over sodium sulfate, the solventwas removed in vacuo and the residue was purified by flashchromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate incyclohexane) to afford an oil which solidified on standing to afford thetitle compound as a white solid (301 mg, 35%). ¹H NMR (CDCl₃, 300MHz):7.23 (d, J=1.7 Hz, 1H), 7.15 (d, J=1.7 Hz, 1H), 3.91 (s, 2H),2.97-2.87 (m, 2H), 2.72-2.62 (m, 2H), 2.15-2.06 (m, 2H), 1.70-1.52 (m,2H), 1.41-1.25 (m, 2H); LCMS (Method B): R_(T)=4.0 min, M+H⁺=260.

Preparation of 1-(2-Bromothiazol-4-ylmethyl)-piperidine

The title compound was prepared from (2-bromothiazol-4-yl)-methanol,following the procedure outlined above for1-(4-bromo-2,6-difluoro-benzyl)-piperidine, to afford the title compoundas a yellow oil. ¹H NMR (CDCl₃, 300 MHz):7.09 (s, 1H), 3.61 (d, J=0.9Hz, 2H), 3.19 (t, J=5.4 Hz, 1H), 2.45 (t, J=5.1 Hz, 4H), 1.69-1.62 (m,4H), 1.48-1.41 (m, 2H). LCMS (Method B): R_(T)=0.8 min, M+H⁺=261/263.

Preparation of Trifluoromethanesulfonic acid3,5-dimethoxy-4-piperidin-1-ylmethyl-phenyl ester

Step 1: 3,5-Dimethoxy-4-piperidin-1-ylmethyl-phenol

A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (0.30 g, 1.65 mmol),piperidine (0.20 mL, 1.98 mmol) and acetic acid (0.47 mL, 8.25 mmol) inmethanol (20 mL) was stirred for 20 minutes before addition of sodiumcyanoborohydride (0.27 g, 4.30 mmol). The reaction mixture was allowedto stir at ambient temperature for 4 h then loaded onto a 10 g SCX-2cartridge which was then washed with methanol (30 mL) and then elutedwith 2N ammonia in methanol (50 mL). Concentration of the combined basicfractions in vacuo afforded the title compound (220 mg, 53%) as a whitesolid. ¹H NMR (DMSO-D₆, 300 MHz): 9.39 (s, 1H), 6.03 (s, 2H), 3.66 (s,6H), 3.30 (s, 2H), 2.32-2.24 (m, 4H), 1.42-1.35 (m, 4H), 1.34-1.26 (m,2H). LCMS (Method B): R_(T)=1.90 min, M+H⁺=252.

Step 2: Trifluoromethanesulfonic acid3,5-dimethoxy-4-piperidin-1-ylmethyl-phenyl ester

To a cooled solution (−20° C.) of3,5-dimethoxy-4-piperidin-1-ylmethyl-phenol (0.22 g, 0.88 mmol) andpyridine (1.0 mL) in DCM (5 mL) was added trifluoromethanesulfonicanhydride (0.18 mL, 1.05 mmol) over 5 minutes. After complete addition,the reaction mixture was allowed to warm to ambient temperature andstirring was continued for 2 h. The resultant mixture was diluted withDCM (50 mL) and washed with water (20 mL). The organic phase wasseparated, dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo. The resultant residue was purified by flash columnchromatography (silica, 5 g, SPE column, 0-50% ethyl acetate incyclohexane) to afford an orange oil which crystallized on standing toyield the title compound (93 mg, 28%). ¹H NMR (CDCl₃, 300 MHz): 6.44 (s,2H), 3.81 (s, 6H), 3.60 (s, 2H), 2.46 (t, J=5.0 Hz, 4H), 1.56 (p, J=5.8Hz, 4H), 1.43-1.36 (m, 2H). LCMS (Method B): R_(T)=2.77 min, M+H⁺=384.

Preparation of 1-(4-Bromo-2-methoxybenzyl)-piperidine

To a stirred solution of 4-bromo-1-chloromethyl-2-methoxybenzene (1.50g, 6.36 mmol) in acetonitrile (64 mL) was added potassium carbonate(1.05 g, 6.36 mmol) and piperidine (0.63 mL, 6.36 mmol) then thereaction mixture was heated under reflux for 15 h. The reaction mixturewas cooled to ambient temperature and then filtered, the filtrate wasthen concentrated under reduced pressure to afford a residue that wasthen loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia inmethanol to afford the title compound (1.73 g, 96%). ¹H NMR (CDCl₃, 300MHz): 7.23 (d, J=8.1 Hz, 1H), 7.05 (dd, J=8.1, 1.9 Hz, 1H), 6.97 (d,J=1.9 Hz, 1H), 3.80 (s, 3H), 3.45 (s, 2H), 2.39 (t, J=5.0 Hz, 4H),1.62-1.51 (m, 4H), 1.47-1.39 (m, 2H).

Preparation of1-[2-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine

A degassed mixture of 1-(4-bromo-2-methoxybenzyl)-piperidine (1.73 g,6.1 mmol), bis(pinacolato)diborane (1.86 g, 7.3 mmol),1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (249 mg,0.31 mmol) and potassium acetate (1.79 mg, 18.3 mmol) in dioxane (31 mL)and DMSO (5 mL) was heated under microwave irradiation at 150° C. for 30minutes. The cooled reaction mixture was diluted with ethyl acetate (100mL) then filtered and the filtrate was washed with water (100 mL). Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to afford the title compound as a beige solid (2.2g, quantitative yield) that was used in the next step without furtherpurification. NMR (CDCl₃, 300 MHz): 7.42 (d, J=0.7 Hz, 2H), 7.29 (s,1H), 3.87 (s, 3H), 3.85 (s, 2H), 2.72-2.64 (m, 4H), 1.74-1.65 (m, 4H),1.50-1.39 (m, 2H), 1.35 (s, 12H).

Preparation of 2-Bromo-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

To a suspension of 2-bromo-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.86g, 8.50 mmol) in THF (30.6 mL) was added acetic acid (17 mL) then thereaction temperature was reduced to 0° C. and sodium borohydride (2.55g, 42.5 mmol) was added in portions. After the addition was complete,the reaction mixture was heated at 60° C. for 1 h then the reactionmixture was cooled to ambient temperature and quenched by the additionof water. The resultant solution was partitioned between ethyl acetate(75 mL) and 1N sodium hydroxide solution (50 mL) and the layersseparated. The organic phase was collected then dried over anhydroussodium sulfate, filtered and evaporated in vacuo to give the titlecompound (1.87 g, 89%). ¹H NMR (MeOD, 300 MHz): 6.78 (s, 1H), 3.50 (s,2H), 2.81 (s, 4H), 2.62 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H).

Preparation of4,4-Dimethyl-1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine

Step 1: 1-(4-Bromobenzyl)-4,4-dimethylpiperidine

A mixture of 4-bromobenzyl bromide (500 mg, 2.0 mmol) and4,4-dimethylpiperidine (249 mg, 2.2 mmol) and potassium carbonate (331mg, 2.4 mmol) in acetonitrile (20 mL) was heated under reflux for 2 h.The reaction mixture was then cooled to ambient temperature and thereaction mixture concentrated under reduced pressure. The resultant oilwas loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia inmethanol to afford the title compound (323 mg, 57%). ¹H NMR (CDCl₃, 300MHz): 7.42 (d, J=8.31 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 3.44 (s, 2H),2.35 (t, J=5.44 Hz, 4H), 1.37 (t, J=5.60 Hz, 4H), 0.90 (s, 6H).

Step 2:4,4-Dimethyl-1-1^(˜)4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine

A degassed mixture of 1-(4-bromobenzyl)-4,4-dimethylpiperidine (320 mg,1.1 mmol), bis(pinacolato)diborane (346 mg, 1.4 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.4 mg,0.06 mmol) and potassium acetate (334 mg, 3.4 mmol) in dioxane (5.8 mL)and DMSO (0.6 mL) was heated under microwave irradiation at 150° C. for30 minutes. The cooled reaction mixture was diluted with ethyl acetate(50 mL) then filtered and the filtrate was washed with water (75 mL).The organic phase was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to afford the title compound as a brown oil (264 mg,71%) that was used in the next step without further purification. ¹H NMR(CDCl₃, 300 MHz): 7.77 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.7 Hz, 2H), 3.63(s, 2H), 2.47 (t, J=5.3 Hz, 4H), 1.43 (t, J=5.6 Hz, 4H), 1.38-1.31 (m,12H), 0.91 (s, 6H).

Preparation of(2S,6R)-2,6-Dimethyl-1-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine

A degassed mixture of (2S,6R)-1-(4-bromobenzyl)-2,6-dimethylpiperidine(1.70 g, 6.0 mmol), bis(pinacolato)diborane (1.83 g, 7.2 mmol),1,1′-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (245 mg,0.3 mmol) and potassium acetate (1.76 mg, 18.0 mmol) in dioxane (31 mL)and DMSO (4 mL) was heated under microwave irradiation at 150° C. for 30minutes. The cooled reaction mixture was diluted with ethyl acetate (100mL) then filtered and the filtrate was washed with water (100 mL). Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to afford the title compound as a beige solid (1.54g, 78%) that was used in the next step without further purification. ¹HNMR (CDCl₃, 300 MHz): 7.75 (d, J=7.7 Hz, 2H), 7.39 (d, J=7.6 Hz, 2H),3.88 (s, 2H), 2.58-2.25 (m, 2H), 1.51-1.70 (m, 4H), 1.43-1.21 (m, 14H),1.10 (d, J=6.2 Hz, 6H).

Preparation of Trifluoromethanesulfonic acid3-methoxy-4-piperidin-1-ylmethyl-phenylester

Step 1: 3-Methoxy-4-piperidin-1-ylmethylphenol

To a pre-stirred solution of 4-hydroxy-2-methoxybenzaldehyde (1.02 g,6.7 mmol), titanium isopropoxide (2.14 mL, 7.0 mmol) and piperidine(0.70 mL, 7.0 mmol) in DCM (20 mL) was added sodiumtriacetoxyborohydride (2.84 g, 13.4 mmol) in portions. After 3 h thereaction mixture was quenched by the addition of methanol (1.0 mL) andthen the solvents were removed under reduced pressure to afford aresidue. The resultant residue was then loaded onto an SCX-2 cartridge(10 g) and eluted with 2N ammonia in methanol to afford the titlecompound (456 mg, 30%). ¹H NMR (CD₃OD, 300 MHz): 7.17 (d, J=8.3 Hz, 1H),6.51 (d, J=2.3 Hz, 1H), 6.43 (dd, J=8.2, 2.2 Hz, 1H), 4.07 (s, 2H), 3.84(s, 3H), 3.16-2.99 (m, 4H), 1.84-1.73 (m, 4H), 1.67-1.56 (m, 2H).

Step 2: Trifluoromethanesulfonic acid3-methoxy-4-piperidin-1-ylmethyl-phenylester

To a stirred solution of 3-methoxy-4-piperidin-1-ylmethylphenol (456 mg,2.06 mmol) and diisopropylamine (0.77 mL, 4.54 mmol) in DCM (10 mL) at0° C. was added N-phenyltriflamide (958 mg, 2.68 mmol). After theaddition was complete the reaction mixture was allowed to warm toambient temperature and then stirred overnight. The reaction mixture wasconcentrated under reduced pressure and then purified by flashchromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM) toafford the title compound as a colourless oil (408 mg, 56%). ¹H NMR(CDCl₃, 300 MHz): 7.60 (d, J=8.4 Hz, 1H), 6.93 (dd, J=8.4, 2.4 Hz, 1H),6.80 (d, J=2.4 Hz, 1H), 3.93 (s, 2H), 3.89 (s, 3H), 2.87-2.74 (m, 4H),1.82-1.75 (m, 4H), 1.57-1.50 (m, 2H).

Preparation of 1-(4-Bromo-2,6-diethylbenzyl)-piperidine

Step 1: 4-Bromo-2,6-diethylbenzonitrile

4-Bromo-2,6-diethylaniline (4.80 g, 21.0 mmol) was suspended in amixture of water (25 mL) and concentrated hydrochloric acid (8.0 mL)then sonicated for 10 minutes. The resultant suspension was cooled to 0°C. and a solution of sodium nitrite (1.60 g, 23.1 mmol) in water (5 mL)was slowly added, maintaining the reaction temperature below 5° C. After30 minutes, the reaction mixture was neutralised by the careful additionof sodium bicarbonate, then the resultant suspension was added inaliquots to a solution of copper (I) cyanide (2.26 g, 25.2 mmol) andpotassium cyanide (3.43 g, 52.6 mmol) in water (25 mL) at 70° C. Aftercomplete addition, heating at 70° C. was continued for 1 h then thereaction mixture was cooled to ambient temperature. Water and DCM wereadded then the organic phase was collected, dried over anhydrous sodiumsulfate and concentrated in vacuo to afford a brown residue that waspurified by flash chromatography (silica, 80 g column, ISCO, 0-10% ethylacetate in cyclohexane) to afford the title compound as an off-whitesolid (4.43 g, 88%). NMR (DMSO-D₆, 300 MHz): 7.58 (s, 2H), 2.78 (q,J=7.6 Hz, 4H), 1.21 (t, J=7.6 Hz, 6H).

Step 2: 4-Bromo-2,6-diethylbenzylamine

Under an inert atmosphere, lithium aluminuium hydride (359 mg, 9.4 mmol)was suspended in anhydrous THF (9 mL) was cooled to 0° C. and then asolution of 4-bromo-2,6-diethylbenzonitrile (1.73 g, 7.36 mmol) inanhydrous THF (3 mL) was added dropwise. The reaction mixture was thenallowed to warm to ambient temperature and stirring was continued for 20h. Sodium sulfate decahydrate (6 g) was then added to quench thereaction and the resultant reaction mixture was filtered then thefiltrate was then evaporated under reduced pressure. The resultant oilwas purified by flash chromatography (silica, 50 g column, ISCO, 0-10%methanol in DCM) to afford the title compound as an orange oil (96 mg,5%). ¹H NMR (DMSO-D₆, 400 MHz): 7.18 (s, 2H), 3.68 (s, 2H), 2.73-2.64(m, 4H), 2.52-2.48 (m, 2H), 1.19-1.11 (m, 6H).

Step 3: 1-(4-Bromo-2,6-diethylbenzyl)-piperidine

4-Bromo-2,6-diethylbenzylamine (90 mg, 0.37 mmol), 1,5-dibromopentane(56 μL, 0.41 mmol) and potassium carbonate (206 mg, 1.5 mmol) weresuspended in dioxane (5 mL) and heated at 100° C. overnight. Thereaction mixture was then cooled to ambient temperature, the solidremoved by filtration and the filtrate concentrated in vacuo to affordan orange oil. The resultant oil was purified by flash chromatography(silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the titlecompound as yellow oil (66 mg, 58%). ¹H NMR (CDCl₃, 300 MHz): 7.16 (s,2H), 3.38 (s, 2H), 2.80-2.62 (m, 4H), 2.35 (s, 4H), 1.54-1.34 (m, 6H),1.27-1.13 (m, 6H).

Preparation of Trifluoromethanesulfonic acid3,5-dichloro-4-piperidin-1-yl methylphenyl ester

Step 1: 3,5-Dichloro-4-piperidin-1-ylmethylphenol

To a pre-stirred solution of 2,6-dichloro-4-hydroxybenzaldehyde (1.88,9.8 mmol) and piperidine (1.07 mL, 10.8 mmol) in DCM (40 mL) was addedsodium triacetoxyborohydride (3.13 g, 14.8 mmol) in portions. After 14 hthe reaction mixture was quenched by the addition of water (50 mL), thepH of the solution adjusted to 2 by the addition of hydrochloric acidand the solution washed with DCM (50 mL). The pH of the aqueous phasewas then adjusted to 9 by the addition of saturated aqueous sodiumcarbonate and then the organic component was extracted with DCM (50 mL),dried over anhydrous sodium sulfate and evaporated under reducedpressure to afford the title compound as a beige solid (2.03 g, 80%)that was used without further purification. ¹H NMR (CD₃OD, 300 MHz):6.81-6.77 (m, 2H), 3.72 (s, 2H), 2.67-2.57 (m, 4H), 1.64-1.54 (m, 4H),1.51-1.44 (m, 2H).

Step 2: Trifluoromethanesulfonic acid3,5-dichloro-4-piperidin-1-ylmethylphenyl ester

To a stirred solution of 3,5-dichloro-4-piperidin-1-ylmethylphenol (290mg, 1.1 mmol) and pyridine (0.36 mL, 4.5 mmol) in DCM (10 mL) at −20° C.was added trifluoromethanesulfonyl chloride (0.38 mL, 2.2 mmol). Afterthe addition was complete the reaction was allowed to warm to ambienttemperature and stirred for 10 minutes. The mixture was diluted with DCM(20 mL), washed with water (10 mL). The organic phase was separated,dried over anhydrous sodium sulfate, filtered and evaporated in vacuo toafford a residue that was purified by flash chromatography (silica, 12 gcolumn, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the titlecompound as a colourless oil (334 mg, 76%). ¹H NMR (CDCl₃, 300 MHz):7.26 (s, 2H), 3.66 (s, 2H), 2.53-2.44 (m, 4H), 1.58-1.48 (m, 4H),1.50-1.34 (m, 2H).

Preparation of Trifluoromethanesulfonic acid3-chloro-5-methoxy-4-piperidin-1-ylmethyl-phenyl ester

Step 1: 1-(2-Chloro-4,6-dimethoxybenzyl)-piperidine

To a pre-stirred solution of 2-chloro-4,6-dimethoxybenzaldehyde (2.7 g,13.5 mmol) and piperidine (1.46 mL, 14.9 mmol) in DCM (50 mL) at 0° C.was added sodium triacetoxyborohydride (4.29 g, 20.0 mmol) in portions.The reaction mixture was then allowed to warm to ambient and stirred foran additional 3 h before the addition of water (50 mL). The pH of theaqueous phase was adjusted to 2 by the addition of hydrochloric acid andthen washed with DCM (50 mL). The pH of the aquous phase was thenadjusted to 9 by the addition of saturated aqueous sodium carbonate andthen the organic component was extracted into DCM (50 mL), dried oversodium sulfate and evaporated under reduced pressure to afford the titlecompound as a beige solid (3.3 g, 91%) that was used without furtherpurification. NMR (CDCl₃, 300 MHz): 6.60 (d, J=2.4 Hz, 1H), 6.43 (d,J=2.4 Hz, 1H), 4.35 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.6-2.57 (v brm, 4H), 2.29-1.88 (br m, 4H), 1.71-1.40 (br m, 2H).

Step 2: 3-Chloro-5-methoxy-4-piperidin-1-ylmethylphenol

Hydroiodic acid (57% solution, 5 mL) was added to1-(2-chloro-4,6-dimethoxybenzyl)-piperidine (360 mg, 1.3 mol) and themixture heated at 60° C. for 2 h. The reaction mixture was cooled toambient temperature, diluted with saturated aqueous sodium carbonatesolution (20 mL) and extracted with DCM (3×30 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo to afford an beige solid that was then purified by flashchromatography (silica, 12 g column, ISCO, 0-15% (2N ammonia inmethanol) in DCM) to afford the title compound as a white solid (277 mg,88%). ¹H NMR (CDCl₃, 400 MHz): 6.08 (d, J=2.2 Hz, 1H), 5.96 (d, J=2.2Hz, 1H), 3.61 (s, 3H), 3.59 (s, 2H), 3.31 (br s, 1H), 2.74-2.64 (m, 4H),1.70-1.62 (m, 4H), 1.60-1.43 (m, 2H).

Step 3: Trifluoromethanesulfonic acid3-chloro-5-methoxy-4-piperidin-1-ylmethylphenyl ester

To a stirred solution of 3-chloro-5-methoxy-4-piperidin-1-ylmethylphenol(223 mg, 0.87 mmol) and pyridine (0.28 mL, 3.5 mmol) in DCM (10 mL) at−20° C. was added trifluoromethanesulfonyl chloride (0.29 mL, 1.7 mmol).After the addition was complete the reaction mixture was allowed to warmto ambient temperature then diluted with DCM (20 mL) then washed withwater (10 mL). The organic phase was separated, dried over anhydroussodium sulfate, filtered and evaporated in vacuo to afford an oil thatwas purified by flash chromatography (silica, 12 g column, ISCO, 0-100%ethyl acetate in cyclohexane) to afford the title compound as a red oil(341 mg, 73%). ¹H NMR (CDCl₃, 300 MHz): 7.06 (d, J=2.3 Hz, 1H), 6.85 (d,J=2.3 Hz, 1H), 4.40 (s, 2H), 4.05 (s, 3H), 3.72-3.42 (m, 1H), 3.06-2.72(m, 1H), 2.23-1.75 (m, 4H), 1.73-1.36 (m, 4H).

Preparation of Trifluoromethanesulfonic acid3-methoxy-5-methyl-4-piperidin-1-ylmethylphenyl ester

Step 1:1-[2-Methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzyl]-piperidine

To a pre-stirred solution of2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzaldehyde (2.14 g, 8.6mmol) and piperidine (0.93 mL, 9.4 mmol) in DCM (35 mL) at 0° C. wasadded sodium triacetoxyborohydride (2.72 g, 12.8 mmol) in portions. Thereaction mixture was allowed to warm to ambient temperature and thenpartitioned between water (30 mL) and ethyl acetate (75 mL). The organicphase was dried over anhydrous sodium sulfate, filtered and evaporatedin vacuo to afford the title compound as a colourless oil (2.78 g,quantitiative yield) that was used in the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz): 6.51 (d, J=2.4 Hz, 1H), 6.45 (d,J=2.4 Hz, 1H), 5.40 (t, J=3.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.76 (s, 3H),3.64-3.55 (m, 1H), 3.39 (s, 2H), 2.42-2.27 (m, 7H), 2.07-1.93 (m, 1H),1.90-1.77 (m, 2H), 1.75-1.52 (m, 3H), 1.54-1.44 (m, 4H), 1.43-1.34 (m,2H).

Step 2: 3-Methoxy-5-methyl-4-piperidin-1-ylmethylphenol

1N Hydrochloric acid (10 mL) was added to1-[2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzyl]-piperidine(2.33 g, 7.3 mmol) in methanol (30 mL) and the reaction mixture wasstirred at ambient temperature for 2 h. The pH of the solution wasadjusted to 9 by the addition of saturated aqueous sodium carbonatesolution (20 mL) and the aqueous phase was extracted with DCM (3×30 mL).The combined organic layer was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford a colourless oil. Theresultant oil was purified by flash chromatography (silica, 12 g column,ISCO, 0-15% (2N ammonia in MeOH) in DCM) to afford the title compound asa white solid (570 mg, 33%). ¹H NMR (CDCl₃, 400 MHz): 6.14 (d, J=2.4 Hz,1H), 5.99 (s, 1H), 3.68 (s, 3H), 3.49 (s, 2H), 2.56-2.46 (m, 4H), 2.25(s, 3H), 1.65-1.51 (m, 4H), 1.48-1.36 (s, 2H).

Step 3: Trifluoromethanesulfonic acid3-methoxy-5-methyl-4-piperidin-1-ylmethylphenyl ester

To a stirred solution 3-methoxy-5-methyl-4-piperidin-1-ylmethylphenol(563 mg, 2.4 mmol) and pyridine (0.77 mL, 10.0 mmol) in DCM (20 mL) at0° C. was added trifluoromethanesulfonyl chloride (0.81 mL, 4.8 mmol).After the addition was complete the reaction was allowed to warm toambient temperature. The mixture was diluted with DCM (20 mL) and washedwith water (10 mL). The organic phase was separated, dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to afford anoil that was purified by flash chromatography (silica, 40 g column,ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compoundas a red oil (698 mg, 58%). NMR (CDCl₃, 300 MHz): 6.82 (d, J=2.4 Hz,1H), 6.73 (d, J=2.4 Hz, 1H), 4.28 (s, 2H), 3.96 (s, 3H), 3.67-3.35 (m,1H), 2.99-2.66 (m, 1H), 2.47 (s, 3H), 2.21-1.75 (m, 4H), 1.73-1.35 (m,4H).

Preparation of 1-(4-Bromo-2-fluorobenzyl)-piperidine

To a pre-stirred solution of 4-bromo-2-fluorobenzaldehyde (1.82 g, 9.0mmol) and piperidine (0.97 mL, 9.9 mmol) in DCM (40 mL) at 0° C. wasadded sodium triacetoxyborohydride (2.85 g, 13.4 mmol) in portions. Thereaction mixture was allowed to warm to ambient temperature and stirredfor an additional 14 h. The reaction was quenched by the addition ofwater (30 mL) and extracted with ethyl acetate (75 mL). The organicphase was separated, dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to afford the title compound as a colourless oil(2.6 g, 84%) that was used in the next step without furtherpurification. NMR (CDCl₃, 400 MHz): 7.33-7.17 (m, 3H), 3.49 (d, J=1.6Hz, 2H), 2.43-2.33 (m, 4H), 1.61-1.53 (m, 4H), 1.46-1.38 (m, 2H).

Preparation of 1-(4-Bromo-2-ethoxybenzyl)-piperidine

Sodium hydride (306 mg, 60%, 7.6 mmol) was added in portions to asolution of 1-(4-bromo-2-fluorobenzyl)-piperidine (520 mg, 1.9 mmol) andethyl urethane (0.91 mL, 7.6 mmol) in dioxane (10 mL) under anatmosphere of nitrogen. The reaction mixture was then sonicated for 30minutes until gas evolution ceased then heated at 140° C. overnight in asealed tube. The reaction mixture was diluted with water and extractedwith DCM (3×30 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and evaporated in vacuo to afford a colourlessoil that was then purified by flash chromatography (silica, 12 g column,ISCO, 0-10% methanol in DCM) to afford the title compound as a whitesolid (416 mg, 74%). ¹H NMR (CDCl₃, 400 MHz): 7.23 (d, J=8.1 Hz, 1H),7.03 (dd, J=8.1, 1.9 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 3.99 (q, J=7.0 Hz,2H), 3.47 (s, 2H), 2.46-2.35 (m, 4H), 1.61-1.53 (m, 4H), 1.45-1.36 (m,5H).

Preparation of 1-(4-Bromo-2-trifluoromethoxybenzyl)-piperidine

To a pre-stirred solution of 4-bromo-2-trifluoromethoxybenzaldehyde(1.82 g, 9.0 mmol) and piperidine (0.97 mL, 9.9 mmol) in DCM (40 mL) at0° C. was added sodium triacetoxyborohydride (2.85 g, 13.4 mmol) inportions. The reaction mixture was then allowed to warm to ambienttemperature and stirred for an additional 14 h. The reaction wasquenched by the addition of water (30 mL) and extracted into ethylacetate (75 mL). The organic phase was sparated, dried over anhydroussodium sulfate, filtered and evaporated in vacuo to afford the titlecompound as a colourless oil (2.6 g, 84%) that was used in the next stepwithout further purification. ¹H NMR (CDCl₃, 300 MHz): 7.47 (d, J=8.2Hz, 1H), 7.41 (d, J=1.9 Hz, 1H), 7.39-7.35 (m, 1H), 3.46 (s, 2H),2.42-2.32 (m, 4H), 1.64-1.51 (m, 4H), 1.48-1.37 (m, 2H).

Preparation of 1-(3-Bromo-5-methoxybenzyl)-piperidine

To a pre-stirred solution of 3-bromo-5-methoxybenzaldehyde (0.56 g, 2.61mmol) and piperidine (0.29 mL, 3.93 mmol) in DCM (10 mL) at 0° C. wasadded sodium borohydride (197 mg, 5.22 mmol) in portions. The reactionmixture was allowed to warm to ambient temperature and stirred for anadditional 2 h. The reaction was quenched by the addition of water (30mL) and extracted into ethyl acetate (75 mL) then washed with water (50mL) then the organic phase was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford the title compound as acolourless oil (510 mg, 69%) that was used in the next step withoutfurther purification. ¹H NMR (CDCl₃, 400 MHz): 7.08-7.06 (m, 1H),6.94-6.91 (m, 1H), 6.83-6.80 (s, 1H), 3.79 (s, 3H), 3.39 (s, 2H),2.40-2.30 (s, 4H), 1.61-1.51 (m, 4H), 1.47-1.38 (m, 2H).

Preparation of 4-[1-(4-Bromobenzyl)-piperidin-4-yl]-morpholine

4-Bromobenzyl bromide (0.5 g, 2.0 mmol) was stirred with4-piperidin-4-yl-morpholine (0.67 g, 4.0 mmol) and triethylamine (0.42mL, 3.0 mmol) in THF (20 mL) at ambient temperature for 28 h then afurther 1.5 eq of triethylamine was added and stirring continued for 16h. The mixture was diluted with water (50 mL) and extracted with ethylacetate (50 mL). The organic phase was separated, dried over anhydroussodium sulfate, filtered and evaporated in vacuo. The resultant residuewas purified by flash chromatography (silica, 12 g column, ISCO, 0-100%ethyl acetate in cyclohexane then 0-10% (2N ammonia in methanol) in DCM)to afford the title compound as an off-white solid (0.62 g, 92%). ¹H NMR(CDCl₃, 400 MHz): 7.44-7.40 (m, 2H), 7.21-7.15 (m, 2H), 3.74-3.69 (m,4H), 3.42 (s, 2H), 2.93-2.85 (m, 2H), 2.56-2.50 (m, 4H), 2.22-2.13 (m,1H), 2.00-1.91 (m, 2H), 1.82-1.74 (m, 2H), 1.59-1.47 (m, 2H).

Preparation of [1-(4-Bromobenzyl)-piperidin-4-yl]-dimethylamine

4-Bromobenzyl bromide (0.5 g, 2.0 mmol) was stirred with4-dimethylaminopiperidine (0.51 g, 4.0 mmol) and triethylamine (0.42 mL,3.0 mmol) in THF (20 mL) at ambient temperature for 96 h. The mixturewas diluted with water (50 mL) and extracted with ethyl acetate (50 mL).The organic phase was separated, dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford the title compound (0.51 g,86%). ¹H NMR (CDCl₃, 400 MHz): 7.44-7.40 (m, 2H), 7.21-7.16 (m, 2H),3.43 (s, 2H), 2.91-2.85 (m, 2H), 2.27 (s, 6H), 2.17-2.07 (m, 1H),2.00-1.91 (m, 2H), 1.80-1.72 (m, 2H), 1.58-1.45 (m, 2H).

Preparation of 4-(4-Bromobenzyl)-2,2-dimethylmorpholine

A mixture of 4-bromobenzyl bromide (1.5 g, 6.0 mmol),2,2-dimethylmorpholine (0.69 g, 6.0 mmol) and potassium carbonate (0.99g, 7.2 mmol) in acetonitrile (60 mL) was heated at 85° C. for 20 h. Themixture was allowed to cool to ambient temperature and the solid wasremoved by filtration and the filtrate evaporated. The resultant residuewas dissolved in DCM/methanol and loaded onto a 20 g SCX-2 cartridgewhich was washed with methanol then 2N ammonia in methanol.Concentration of the combined basic fractions afforded the titlecompound (1.65 g, 97%) as an orange oil. ¹H NMR (CDCl₃, 300 MHz): 7.44(d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 3.75 (t, J=4.8 Hz, 2H), 3.39(s, 2H), 2.37 (t, J=4.6 Hz, 2H), 2.16 (s, 2H), 1.23 (s, 6H).

Preparation of cis-4-(4-Bromo-2-ethoxybenzyl)-2,6-dimethylmorpholine

Step 1: cis-4-(4-Bromo-2-fluorobenzyl)-2,6-dimethylmorpholine

To a suspension of 4-bromo-2-fluorobenzyl bromide (1.0 g, 3.7 mmol) andpotassium carbonate (0.61 g, 4.4 mmol) in THF (37 mL) was addedcis-2,6-dimethylmorpholine (0.43 g, 3.7 mmol). The reaction mixture washeated under reflux for 6 h and then cooled, the solid removed byfiltration and the filtrate was evaporated. The resultant residue wasloaded onto a 10 g SCX-2 cartridge which was washed with methanol then2N ammonia in methanol. Concentration of the combined basic fractions invacuo afforded the title compound (76 mg, 7%). ¹H NMR (CDCl₃, 300 MHz):7.28-7.19 (m, 3H), 3.73-3.59 (m, 2H), 3.49 (d, J=1.5 Hz, 2H), 2.71-2.64(m, 2H), 1.86-1.73 (m, 2H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G):R_(T)=2.84 min, M+H⁺=302.

Step 2: cis-4-(4-Bromo-2-ethoxybenzyl)-2,6-dimethylmorpholine

To a solution of cis 4-(4-bromo-2-fluorobenzyl)-2,6-dimethylmorpholine(0.76 g, 2.5 mmol) in 1,4-dioxane (7.5 mL) under nitrogen was addedethyl urethane (1.2 mL, 10.0 mmol) followed by portionwise addition ofsodium hydride (60% dispersion in mineral oil, 0.40 g, 10.0 mmol). Thereaction mixture was heated at 100° C. for 24 h then partitioned betweenDCM and water and the phases were separated. The aqueous phase wasfurther extracted with DCM and the combined organic layers were driedover sodium sulfate, filtered and evaporated. The residue was purifiedby flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetatein pentane) to afford the title compound (0.114 g, 14%). ¹H NMR (CD₃ODand CDCl₃, 300 MHz): 7.22 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.1, 1.9 Hz,1H), 6.97 (d, J=1.9 Hz, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.75-3.62 (m, 2H),3.47 (s, 2H), 2.75-2.66 (m, 2H), 1.86-1.76 (m, 2H), 1.41 (t, J=7.0 Hz,3H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G): R_(T)=3.24 min, M+H⁺=328.

Preparation of 2-Bromo-4,5,6,7-tetrahydrobenzo[b]thiophene

Step 1: 4,5,6,7-Tetrahydrobenzo[b]thiophene

Aluminium trichloride (0.61 g, 4.60 mmol) in anhydrous diethyl ether (5mL) was placed under an atmosphere of argon and lithium aluminiumhydride (1M in diethyl ether, 4.6 mL, 4.60 mmol) was added dropwise. Theresultant solution was stirred for 2 minutes and then a solution of6,7-dihydro-4-benzo[b]thiophen-4-one (0.59 g, 3.83 mmol) in diethylether (10 mL) was added dropwise. The reaction mixture was stirred atambient temperature for 4.5 h then was quenched with water (5 mL)followed by 6M sulfuric acid (10 mL) before being extracted into diethylether (4×15 mL). The combined organic phase was washed with water (20mL) and brine, dried over sodium sulfate, filtered and evaporated toafford the title compound (0.49 g, 91%). ¹H NMR (CDCl₃, 300 MHz): 7.04(d, J=5.2 Hz, 1H), 6.75 (d, J=5.1 Hz, 1H), 2.83-2.72 (m, 2H), 2.67-2.59(m, 2H), 1.89-1.74 (m, 4H).

Step 2: 2-Bromo-4,5,6,7-tetrahydrobenzo[b]thiophene

4,5,6,7-Tetrahydrobenzo[b]thiophene (0.252 g, 1.79 mmol) was dissolvedin chloroform (10 mL), cooled to 0° C. and N-bromosuccinimide (0.334 g,1.88 mmol) was added. The reaction mixture was stirred at 0° C. for 1 hthen at ambient temperature for 1.75 h and then heated at 40° C. for afurther 4 h. The reaction mixture was cooled to room temperature,concentrated in vacuo and the residue diluted with water and extractedwith diethyl ether (4×10 mL). The combined organic phase was washed withwater and brine, dried over sodium sulfate, filtered and evaporated toafford the title compound (0.35 g, 88%) as a brown oil. ¹H NMR (CDCl₃,300 MHz): 6.69 (s, 1H), 2.73-2.59 (m, 2H), 2.58-2.49 (m, 2H), 1.88-1.70(m, 4H).

Preparation of 6-(4-Bromobenzyl)-2-oxa-6-aza-spiro[3.3]heptane

A mixture of 2-oxa-6-aza-spiro[3.3]heptane (−3.72 mmol), 4-bromobenzylbromide (0.39 g, 1.54 mmol), potassium carbonate (0.64, 4.63 mmol) andsodium iodide (11 mg, 0.08 mmol) in THF (10 mL) was stirred at ambienttemperature for 16 h. The solid was removed by filtration, washed withTHF and the combined filtrate was evaporated. The resultant residue waspurified by flash chromatography (silica, 12 g column, ISCO, 0-100%ethyl acetate in pentane then 10% methanol in DCM) to afford the titlecompound (0.28 g, 68%) as a viscous oil which crystallised on standingto a pale yellow solid. ¹H NMR (CDCl₃, 300 MHz): 7.46-7.40 (m, 2H),7.15-7.09 (m, 2H), 4.73 (s, 4H), 3.48 (s, 2H), 3.35 (s, 4H).

Preparation of 1-[2-(4-Bromophenyl)-ethyl]-piperidine

Methanesulfonyl chloride (0.43 mL, 5.47 mmol) was added to a solution of2-(4-bromophenyl)-ethanol (1.0 g, 4.97 mmol) and triethylamine (0.84 mL,5.96 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at0° C. for 15 minutes then at ambient temperature for 2 h. The reactionmixture was partitioned between water and DCM and the organic phase wasdried over sodium sulfate, filtered and evaporated to give a colourlessoil. The resultant residue was dissolved in acetonitrile (10 mL),piperidine (0.491 mL, 4.97 mmol) and potassium carbonate (0.823 g, 5.96mmol) were added and the reaction mixture was heated at 70° C. for 2.5h. The reaction mixture was allowed to cool to ambient temperature thenpartitioned between ethyl acetate and water. The organic phase was driedover sodium sulfate, filtered and evaporated and the resultant residuedissolved in methanol and loaded onto a 10 g SCX-2 cartridge. The columnwas washed with methanol then eluted with 2N ammonia in methanol and thebasic fractions were evaporated to afford the title compound (1.27 g,95%) as a colourless oil. ¹H NMR (CDCl₃, 300 MHz): 7.41-7.36 (m, 2H),7.10-7.04 (m, 2H), 2.79-2.71 (m, 2H), 2.54-2.40 (m, 6H), 1.66-1.56 (m,4H), 1.50-1.40 (m, 2H).

Preparation of 1-(4-Bromobenzyl)-3-methyl-piperidin-3-ol

A mixture of 4-bromobenzyl bromide (0.50 g, 2.0 mmol), triethylamine(0.42 mL, 3.0 mmol) and 3-methyl-piperidin-3-ol (0.46 g, 4.0 mmol) inTHF (20 mL) was stirred at ambient temperature for 16 h. The reactionmixture was evaporated and the resultant residue diluted with saturatedaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×50 mL). The combined organic layer was dried over sodium sulfate,filtered and evaporated to afford the title compound (0.50 g, 88%). ¹HNMR (CDCl₃, 300 MHz): 7.49-7.43 (m, 2H), 7.23-7.15 (m, 2H), 3.78 (s,2H), 3.69-3.59 (m, 2H), 2.63-2.51 (m, 2H), 2.14 (br s, 1H), 1.77-1.49(m, 4H), 1.15 (s, 3H).

Preparation of 1-(4-Bromobenzyl)-4-methoxy-4-methylpiperidine

Step 1: 4-Hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester(2.0 g, 10.05 mmol) in diethyl ether (20 mL) at −25 to −30° C. was addedmethyl magnesium bromide (3M in diethyl ether, 3.35 mL, 10.05 mmol)dropwise under argon. The reaction mixture was allowed to warm to roomtemperature and stirred for 2 h. Water (20 mL) was then added dropwise,followed by saturated ammonium chloride (20 mL) and the ether layer wasseparated. The aqueous phase was further extracted with ether (50 mL)and the combined organic layer was dried over sodium sulfate, filteredand evaporated to afford the title compound (2.09 g, 97%). ¹H NMR(CDCl₃, 300 MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m, 2H), 2.48-2.39 (m,1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s, 3H).

Step 2: 4-Methoxy-4-methylpiperidine

A suspension of sodium hydride (60% dispersion in mineral oil, 0.44 g,11.66 mmol) in DMF (20 mL) was cooled to 0° C. then4-hydroxy-4-methylpiperidine-1-carboxylic acid tert-butyl ester (2.09 g,9.72 mmol) in DMF (5 mL) was added. The reaction mixture was stirred atroom temperature for 1 h then sodium iodide (3.03 mL, 48.6 mmol) wasadded and stirring continued at room temperature for 16 h then heated at70° C. for 16 h. The reaction mixture was allowed to cool to roomtemperature and ice-cold brine was added before the mixture wasextracted with ethyl acetate (2×100 mL). The combined organic phase wasdried over sodium sulfate, filtered and evaporated and the resultantresidue was purified by flash chromatography (silica, Biotage 50 gcolumn, 0-20% ethyl acetate in cyclohexane) to afford a colourless oil(0.94 g). The resultant oil was dissolved in DCM (5 mL) and TFA (5 mL)and stirred at ambient temperature for 2 h. The reaction mixture wasloaded onto an SCX-2 cartridge which was washed with acetonitrile andmethanol then eluted with 2N ammonia in methanol. The basic methanolfractions were evaporated to afford the title compound (0.50 g, 40%) ¹HNMR (CDCl₃, 300 MHz): 3.19 (s, 3H), 2.96-2.85 (m, 2H), 2.81-2.70 (m,2H), 1.79-1.66 (m, 2H), 1.51-1.38 (m, 2H), 1.15 (s, 3H) plus 1exchangeable not observed.

Step 3: 1-(4-Bromobenzyl)-4-methoxy-4-methylpiperidine

A mixture of 4-bromobenzyl bromide (0.44 g, 1.74 mmol), triethylamine(0.37 mL, 2.61 mmol) and 4-methoxy-4-methylpiperidine (0.45 g, 3.49mmol) in THF (10 mL) was stirred at ambient temperature for 16 h. Thesolvent was evaporated and the resultant residue was diluted withsaturated aqueous sodium bicarbonate solution and extracted with ethylacetate (2×50 mL). The combined organic layer was dried over sodiumsulfate, filtered and evaporated to afford the title compound as ayellow oil (0.50 g, 96%). ¹H NMR (CDCl₃, 300 MHz): 7.45-7.39 (m, 2H),7.22-7.17 (m, 2H), 3.44 (s, 2H), 3.17 (s, 3H), 2.52-2.42 (m, 2H),2.36-2.25 (m, 2H), 1.79-1.70 (m, 2H), 1.59-1.47 (m, 2H), 1.13 (s, 3H).

Preparation of 4-(4-Bromobenzyl)-thiomorpholine

A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine(0.84 mL, 6.0 mmol) and thiomorpholine (0.82 mL, 8.0 mmol) in THF (10mL) was stirred at ambient temperature for 16 h. The solvent wasevaporated and the resultant residue diluted with saturated aqueoussodium bicarbonate solution and extracted with ethyl acetate (2×50 mL).The combined organic layer was dried over sodium sulfate, filtered andevaporated to afford the title compound as an off-white solid (1.13 g,quantitative yield). ¹H NMR (CDCl₃, 300 MHz): 7.46-7.40 (m, 2H),7.21-7.16 (m, 2H), 3.45 (s, 2H), 3.15-3.09 (m, 1H), 2.76-2.60 (m, 6H),2.62-2.57 (m, 1H).

Preparation of 4-(4-Bromobenzyl)-thiomorpholine 1,1-dioxide

A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine(0.84 mL, 6.0 mmol) and thiomorpholine 1,1-dioxide (1.09 g, 8.0 mmol) inTHF (10 mL) was stirred at ambient temperature for 16 h. The solvent wasevaporated and the resultant residue diluted with saturated aqueoussodium bicarbonate solution and extracted with ethyl acetate (2×50 mL).The combined organic layer was dried over sodium sulfate, filtered andevaporated to afford the title compound (0.90 g, 74%). ¹H NMR (CDCl₃,300 MHz): 7.50-7.44 (m, 2H), 7.22-7.16 (m, 2H), 3.60 (s, 2H), 3.09-3.02(m, 4H), 3.00-2.94 (m, 4H).

Preparation of 4-(4-Bromobenzyl)-thiomorpholine 1-oxide

A mixture of 4-(4-bromobenzyl)-thiomorpholine (0.20 g, 0.735 mmol) wasdissolved in DCM (10 mL) under a nitrogen atmosphere andm-chloroperbenzoic acid (0.13 g, 0.74 mmol) was added portionwise. Thereaction mixture was stirred at room temperature for 1 h then purifiedby flash chromatography (silica, Biotage 50 g column, 0-75% (10%methanol in DCM)) to afford the title compound (0.125 g, 59%). ¹H NMR(DMSO-D₆, 400 MHz): 7.55-7.49 (m, 2H), 7.31-7.25 (m, 2H), 3.53 (s, 2H),2.92-2.80 (m, 4H), 2.78-2.65 (m, 2H), 2.64-2.54 (m, 2H). LCMS (MethodG): R_(T)=2.66 min, M+H⁺=289.

Preparation of 4-(4-Bromobenzyl)-piperazin-2-one

A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine(0.84 mL, 6.0 mmol) and piperazin-2-one (0.81 g, 8.0 mmol) in THF (20mL) was stirred at ambient temperature for 16 h. The solvent wasevaporated and the resultant residue diluted with saturated aqueoussodium bicarbonate solution and extracted with ethyl acetate (2×50 mL).The combined organic layer was dried over sodium sulfate, filtered andevaporated to afford the title compound (1.0 g, 93%). ¹H NMR (CDCl₃, 300MHz): δ 7.49-7.43 (m, 2H); 7.24-7.16 (m, 2H); 6.20 (s, 1H); 3.53 (s,2H); 3.38-3.32 (m, 2H); 3.15 (s, 2H); 2.66-2.59 (m, 2H).). LCMS (MethodG): R_(T)=2.54 min, M−H⁺=268.

Preparation of (4-Bromobenzyl)-diethylamine

A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine(0.84 mL, 6.0 mmol) and diethylamine (0.84 mL, 8.0 mmol) in THF (20 mL)was stirred at ambient temperature for 16 h. The solvent was evaporatedand the resultant residue diluted with saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate (2×50 mL). Thecombined organic layer was dried over sodium sulfate, filtered andevaporated to afford the title compound (0.85 g, 88%). ¹H NMR (CDCl₃,300 MHz): 7.45-7.38 (m, 2H), 7.27-7.18 (m, 2H), 3.50 (s, 2H), 2.50 (q,J=7.1 Hz, 4H), 1.03 (t, J=7.1 Hz, 6H). LCMS (Method G): R_(T)=1.98 min,M−H⁺=242.

Preparation of (S)-1-(4-Bromobenzyl)-piperidin-3-ol

A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine(0.84 mL, 6.0 mmol) and (S)-3-methyl-piperidin-3-ol (1.11 g, 8.0 mmol)in THF (20 mL) was stirred at ambient temperature for 16 h. The solventwas evaporated and the resultant residue diluted with saturated aqueoussodium bicarbonate solution and extracted with ethyl acetate (2×50 mL).The combined organic layer was dried over sodium sulfate, filtered andevaporated. The resultant residue was purified by flash chromatography(silica, Biotage 50 g column, 50-100% ethyl acetate in cyclohexane) toafford the title compound (0.8 g, 74%). ¹H NMR (CDCl₃, 300 MHz):7.46-7.40 (m, 2H), 7.21-7.14 (m, 2H), 3.85-3.76 (m, 1H), 3.45 (s, 2H),2.45 (s, 3H), 2.29-2.16 (m, 1H), 1.86-1.70 (m, 1H), 1.67-1.45 (m, 3H)plus 1 exchangeable not observed. LCMS (Method G): R_(T)=1.42 min,M+H⁺=270.

Preparation of (R)-1-(4-Bromobenzyl)-piperidin-3-ol

A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine(0.84 mL, 6.0 mmol) and (R)-3-methyl-piperidin-3-ol (1.11 g, 8.0 mmol)in THF (20 mL) was stirred at ambient temperature for 16 h. The solventwas evaporated and the resultant residue diluted with saturated aqueoussodium bicarbonate solution and extracted with ethyl acetate (2×50 mL).The combined organic layer was dried over sodium sulfate, filtered andevaporated. The material was purified by flash chromatography (silica,Biotage 50 g column, 50-100% ethyl acetate in cyclohexane) to afford thetitle compound (0.75 g, 69%). ¹H NMR (CDCl₃, 300 MHz): 7.46-7.40 (m,2H), 7.21-7.14 (m, 2H), 3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H),2.29-2.16 (m, 1H), 1.86-1.70 (m, 1H) 1.67-1.45 (m, 3H) plus 1exchangeable not observed. LCMS (Method G): R_(T)=2.00 min, M+H⁺=270.

Preparation of 4-(3-Bromophenyl)-1-methyl-piperidine

A mixture of 4-(3-bromophenyl)-1-N-Boc piperidine (430 mg, 1.26 mmol),formic acid (5 mL) and formaldehyde (0.5 mL) was heated under microwaveirradiation at 150° C. for 10 minutes. The cooled reaction mixture wasloaded onto a 70 g SCX-2 cartridge which was washed with methanol (200mL) and then eluted with 2N ammonia in methanol (200 mL). Concentrationof the combined basic fractions in vacuo afforded the title compound(318 mg, 99%) as a brown oil. ¹H NMR (CDCl₃, 300 MHz): 7.38-7.36 (m,1H); 7.35-7.29 (m, 1H); 7.17-7.14 (m, 2H); 3.03-2.92 (m, 2H); 2.52-2.37(m, 1H); 2.32 (s, 3H); 2.10-1.99 (m, 2H); 1.87-1.69 (m, 4H).

Preparation of 3-(4-Bromophenyl)-3-hydroxypiperidine-1-carboxylic acidtert-butyl ester

n-Butyllithium (2.5 M in hexanes, 8.2 mL, 20.5 mmol) was added over 10min to a solution of 1-bromo-4-iodobenzene (5.79 g, 20.5 mmol) in THF(100 mL) at −78° C. After 15 min, a solution of 1-boc-3-piperidone (3.71g, 18.6 mmol) in THF (10 mL) was added and the resultant reactionmixture was left to stir at −78° C. for 1 h, then warmed to 0° C. andquenched by the addition of saturated aqueous ammonium chloride (50 mL).The mixture was allowed to warm to ambient temperature and partitionedbetween ethyl acetate (400 mL) and water (150 mL). The organic layer wasseparated, dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo. The resultant residue was purified by flashchromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate incyclohexane) to afford the title compound as a colourless gum (3.69 g,56%). ¹H NMR (CDCl₃, 300 MHz): 7.52-7.46 (m, 2H); 7.42-7.36 (m, 2H);4.16-3.87 (m, 2H); 3.13 (d, J=13.7 Hz, 1H); 2.92-2.77 (m, 1H); 2.03-1.53(m, 4H); 1.47 (s, 9H).

Preparation of 3-(4-Bromo-phenyl)-1-methyl-piperidin-3-ol

A mixture of 3-(4-bromo-phenyl)-3-hydroxypiperidine-1-carboxylic acidtert-butyl ester (1.39 g, 3.9 mmol), formic acid (18.4 mL) andformaldehyde (1.6 mL) was heated under microwave irradiation at 150° C.for 5 minutes. The cooled reaction mixture was loaded onto a 70 g SCX-2cartridge which was washed with methanol (200 mL) and then eluted with2N ammonia in methanol (200 mL). Concentration of the combined basicfractions in vacuo afforded the title compound (978 mg, 93%) as a brownoil. LCMS (Method B): R_(T)=1.84 min, M+H⁺=270.

Preparation of 3-(3-Bromophenyl)-3-hydroxypiperidine-1-carboxylic acidtert-butyl ester

n-Butyllithium (2.5 M in hexanes, 7.6 mL, 19.0 mmol) was added over 10min to a solution of 1-bromo-3-iodobenzene (5.37 g, 19.0 mmol) in THF(100 mL) at −78° C. After 15 min, a solution of 1-boc-3-piperidone (3.44g, 17.3 mmol) in THF (10 mL) was added and the resultant reactionmixture was left to stir at −78° C. for 1 h, then warmed to 0° C. andquenched by the addition of saturated aqueous ammonium chloride (50 mL).The mixture was allowed to warm to ambient temperature and partitionedbetween ethyl acetate (400 mL) and water (150 mL). The organic layer wasseparated, dried over anhydrous magnesium sulfate, filtered andevaporated in vacuo. The resultant residue was purified by flashchromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate incyclohexane) to afford the title compound as a colourless gum (1.99 g,33%). NMR (CDCl₃, 300 MHz): 7.70-7.67 (m, 1H); 7.46-7.40 (m, 2H);7.24-7.20 (m, 1H); 4.15-3.88 (m, 2H); 3.21-3.08 (m, 1H); 2.93-2.79 (m,1H); 2.03-1.82 (m, 2H); 1.75-1.51 (m, 2H); 1.48 (s, 9H). LCMS (MethodB): R_(T)=3.88 min, M-[Boc-18]⁺238.

Preparation of 4-[(3,3-Dimethylpyrrolidine)-methyl]phenyl boronic acid

A mixture of 4-(bromomethyl)benzene boronic acid (565 mg, 2.63 mmol),3,3-dimethylpyrrolidine (390 mg, 3.94 mmol), potassium carbonate (1.09g, 7.88 mmol) and sodium iodide (20 mg, 0.13 mmol) in acetonitrile (30mL) were stirred at ambient temperature for 18 h. The resultant reactionmixture was evaporated in vacuo to afford the crude title compound as ayellow solid (quantitative yield), which was used without furtherpurification. LCMS (Method B): R_(T)=1.69 min, M+H⁺=234

Preparation of 4-[(3,3-Difluoropyrrolidine)-methyl]phenyl boronic acid

A mixture of 4-(bromomethyl)benzene boronic acid (517 mg, 2.40 mmol),3,3-difluoropyrrolidine hydrochloride (415 mg, 2.89 mmol), potassiumcarbonate (1.33 g, 9.62 mmol) and sodium iodide (18 mg, 0.12 mmol) inacetonitrile (30 mL) were stirred at ambient temperature for 18 h. Theresultant reaction mixture was evaporated in vacuo to afford the crudetitle compound as a white solid (quantitative yield), which was usedwithout further purification. ¹H NMR (MeOD, 300 MHz): 7.48 (d, J=7.7 Hz,2H); 7.11 (d, J=7.7 Hz, 2H); 3.58 (s, 2H); 2.89-2.70 (m, 4H); 2.32-2.14(m, 2H). LCMS (Method B): R_(T)=1.46 min, M+H⁺=242.

Preparation of 4-[(3-Trifluoromethylpiperidine)-methyl]phenyl boronicacid

A mixture of 4-(bromomethyl)benzene boronic acid (473 mg, 2.20 mmol),3-trifluoromethylpiperidine (403 mg, 2.63 mmol) and potassium carbonate(910 mg, 6.60 mmol) in acetonitrile (30 mL) were stirred at ambienttemperature for 18 h. The reaction mixture was evaporated in vacuo andthe resultant residue suspended in MeOH and the solid removed byfiltration. The filtrate was evaporated to afford the title compound asa yellow solid (quantitative yield), which was used without furtherpurification. ¹H NMR (MeOD, 300 MHz): 7.49 (d, J=7.6 Hz, 2H); 7.11 (d,J=7.7 Hz, 2H); 3.56-3.43 (m, 2H); 3.10-3.01 (m, 1H); 2.98-2.88 (m, 1H);2.46-2.24 (m, 1H); 2.00-1.85 (m, 3H); 1.81-1.70 (m, 1H); 1.67-1.43 (m,1H); 1.34-1.14 (m, 1H). LCMS (Method G): R_(T)=1.85 min, M+H⁺=288.

Preparation of 4-[(3-Fluoropiperidine)-methyl]phenyl boronic acid

A mixture of 4-(bromomethyl)benzene boronic acid (419 mg, 1.95 mmol),3-fluoropiperidine (326 mg, 2.34 mmol) and potassium carbonate (1.08 g,7.71 mmol) in acetonitrile (30 mL) were stirred at ambient temperaturefor 18 h. The reaction mixture was evaporated in vacuo and the resultantresidue suspended in MeOH and the solid removed by filtration. Thefiltrate was evaporated to afford the title compound as a yellow solid(quantitative yield), which was used without further purification. ¹HNMR (MeOD, 300 MHz): 7.48 (d, J=7.6 Hz, 2H); 7.11 (d, J=7.7 Hz, 2H);4.72-4.44 (m, 1H); 3.50 (s, 2H); 2.77-2.60 (m, 1H); 2.54-2.27 (m, 3H);1.90-1.73 (m, 2H); 1.67-1.44 (m, 2H). LCMS (Method G): R_(T)=1.35 min,M+H⁺=238.

Preparation of 1-(4-Bromobenzyl)-piperidine-4-carbonitrile

A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine(0.84 mL, 6.0 mmol) and piperidine-4-carbonitrile (880 mg, 8.0 mmol) inTHF (20 mL) was stirred at ambient temperature for 18 h. The reactionmixture was evaporated in vacuo and the residue partitioned betweensaturated sodium bicarbonate solution (100 mL) and dichloromethane (100mL). The organic phase was separated, dried over sodium sulfate,filtered and evaporated in vacuo. The resultant residue was purified byflash chromatography (silica, Biotage 50 g column, 0-100% ethyl acetatein cyclohexane) to afford the title compound (1.10 g, 99%). ¹H NMR(CDCl₃, 300 MHz): 7.46-7.41 (m, 2H); 7.21-7.15 (m, 2H); 3.44 (s, 2H);2.70-2.57 (m, 3H); 2.38-2.22 (m, 2H); 1.99-1.74 (m, 4H). LCMS (MethodB): R_(T)=1.82 min, M+H⁺=280.

Preparation of (4-Bromo-2-methoxy-benzyloxy)-tert-butyldimethylsilane

tert-Butyldimethylsilyl chloride (1.04 g, 6.9 mmol) was added to amixture of (4-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mol) andimidazole (470 mg, 7.0 mmol) in DMF (15 mL) and the resultant mixturewas stirred at ambient temperature for 66 h. The mixture wasconcentrated to about a third of the original volume then diluted withwater and extracted with diethyl ether (×3). The combined organic layerwas dried over magnesium sulfate, filtered and evaporated. The resultantresidue was purified by chromatography (silica, 50 g column, Si-SPE, 5%diethyl ether in pentane) to afford the title compound as a colourlessoil (1.51 g, 98%). ¹H NMR (CDCl₃, 400 MHz): 7.34 (dt, J=8.1, 1.05 Hz,1H); 7.11 (dd, J=8.1, 1.8 Hz, 1H); 6.95 (d, J=1.8 Hz, 1H); 4.69 (d,J=1.0 Hz, 2H); 3.81 (s, 3H); 0.97-0.94 (m, 9H); 0.13-0.08 (m, 6H).

Preparation of cis-1-(4-Bromobenzyl)-3,5-dimethylpiperidine andtrans-1-(4-Bromobenzyl)-3,5-dimethylpiperidine

A suspension of 4-bromobenzyl bromide (4.0 g, 16.0 mmol), cis,trans-(3,5-dimethylpiperidine) (1.81 g, 16.0 mmol) and potassiumcarbonate (2.65 g, 19.2 mmol) in THF (160 mL) was heated under refluxfor 24 h. The reaction mixture was allowed to cool to ambienttemperature, the solid removed by filtration and the filtrate evaporatedin vacuo. The resultant residue was loaded onto a 50 g SCX-2 cartridgewhich was washed with methanol then eluted with 2N ammonia in methanol.Concentration of the combined basic fractions in vacuo followed by flashchromatography of the resultant residue (silica, 330 g column, ISCO,0-25% ethyl acetate in pentane) affordedcis-1-(4-bromobenzyl)-3,5-dimethylpiperidine (1.60 g, 35%) as acolourless oil. ¹H NMR (CDCl₃, 300 MHz): 7.47-7.39 (m, 2H); 7.20 (d,J=8.0 Hz, 2H); 3.42 (s, 2H); 2.82-2.71 (m, 2H); 1.76-1.61 (m, 4H);1.51-1.37 (m, 2H); 0.82 (d, J=6.4 Hz, 6H).

Further elution furnished trans-1-(4-bromobenzyl)-3,5-dimethylpiperidine(956 mg, 21%) as a colourless oil. ¹H NMR (CDCl₃, 300 MHz): 7.42 (d,J=8.2 Hz, 2H); 7.21 (d, J=8.1 Hz, 2H); 3.46-3.26 (m, 2H); 2.40-2.28 (m,2H); 2.08-1.96 (m, 2H); 1.95-1.80 (m, 2H); 1.32-1.23 (m, 2H); 0.94 (d,J=6.7 Hz, 6H).

Preparation of 1-(4-Bromo-2-chloro-benzyl)-piperidine

To a pre-stirred solution of 4-bromo-2-chlorobenzaldehyde (1.01 g, 4.6mmol) and piperidine (500 μL, 5.0 mmol) in DCM (20 mL) at 0° C. wasadded sodium triacetoxyborohydride (1.46 g, 6.9 mmol) in portions. Thereaction mixture was allowed to warm to ambient temperature and thenpartitioned between water (50 mL) and dichloromethane (50 mL). Theorganic phase was separated, washed with saturated aqueous sodiumcarbonate (50 mL), dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The resultant residue was loaded onto a 20 g SCX-2cartridge which was washed with methanol then 2N ammonia in methanol.Concentration of the combined basic fractions in vacuo afforded thetitle compound as a colourless oil (1.15 g, 87%). ¹H NMR (CDCl₃, 400MHz): 7.50-7.48 (m, 1H); 7.40-7.33 (m, 2H); 3.50 (s, 2H); 2.46-2.38 (m,4H); 1.62-1.53 (m, 4H); 1.49-1.40 (m, 2H). LCMS (Method B): R_(T)=2.03min, M+H⁺=288.

Preparation of (4-Bromobenzyloxy)-tert-butyldimethylsilane

tert-Butyldimethylsilyl chloride (2.42 g, 16 mmol) was added to amixture of (4-bromophenyl)methanol (2.0 g, 107 mmol) and imidazole (1.09g, 16 mmol) in DMF (30 mL) and the resultant mixture was stirred atambient temperature for 72 h. The mixture was concentrated to one thirdof the original volume then diluted with water (50 mL) and extractedwith diethyl ether (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo. Theresultant residue was purified by chromatography (silica, 50 g column,Si-SPE, 0-5% diethyl ether in pentane) to afford the title compound as acolourless oil (3.21 g, 100%). ¹H NMR (CDCl₃, 400 MHz): 7.45-7.42 (m,2H); 7.21-7.17 (m, 2H); 4.68 (s, 2H); 0.93 (s, 9H); 0.09 (s, 6H).

Preparation of[1-(4-Bromophenyl)-1-methylethoxy]-tert-butyldimethylsilane

tert-Butyldimethylsilyl chloride (2.10 g, 14 mmol) was added to amixture of 2-(4-bromophenyl)-propan-2-ol (2.0 g, 9.3 mmol) and imidazole(0.95 g 14 mmol) in DMF (30 mL) and the resultant mixture was stirred at80° C. for 24 h. The mixture was concentrated to one third of theoriginal volume then diluted with water (50 mL) and extracted withdiethyl ether (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and evaporated in vacuo. Theresultant residue was purified by chromatography (silica, 50 g column,Si-SPE, 0-5% diethyl ether in pentane) to afford the title compound as acolourless oil (1.39 g, 46%). ¹H NMR (MeOD, 400 MHz): 7.46-7.37 (m, 4H);1.56 (s, 6H); 0.95-0.91 (m, 9H); 0.06 (s, 6H).

Preparation of 1-(5-Tributylstannanylisothiazol-3-ylmethyl)-piperidine

Step 1: 1-(5-Bromoisothiazol-3-ylmethyl)-piperidine

5-Bromo-3-bromomethylisothiazole (1.92 g, 7.5 mmol), triethylamine (1.57mL, 11.2 mmol) and piperidine (1.5 mL, 15.0 mmol) in DCM (10 mL) werestirred for 16 h at ambient temperature. The reaction mixture waspartitioned between water (50 mL) and ethyl acetate (75 mL). The organicphase was separated, dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to afford the title compound as a colourless oil(1.49 g, 97%) that was used in the next step without furtherpurification. ¹H NMR (CDCl₃, 400 MHz): 7.25 (s, 1H), 3.59 (s, 2H),2.46-2.33 (m, 4H), 1.62-1.53 (m, 4H), 1.48-1.38 (m, 2H).

Step 2: 1-(5-Tributylstannanylisothiazol-3-ylmethyl)-piperidine

To a cold (−78° C.) solution of nBuLi (2.5M in hexanes, 0.88 mL, 0.35mmol) in anhydrous THF (20 mL) was added diisopropylamine (0.32 mL, 2.2mmol). The solution was allowed to warm to −20° C. for 30 minutes thencooled to −78° C. before addition of a solution of(1-(5-bromoisothiazol-3-ylmethyl)-piperidine (600 mg, 1.2 mmol) inanhydrous THF (5 mL). After 30 minutes, the reaction mixture was allowedto warm to ambient tempertaure and saturated aqueous sodium hydrogencarbonate was added. The aqueous phase was extracted with DCM (3×50 mL),the combined organic phase was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford a colourless oil that waspurified by flash chromatography (silica, 12 g column, ISCO, 0-40%acetone in DCM) to afford the title compound as a colourless oil (110mg, 73%). ¹H NMR (CDCl₃, 400 MHz): 7.23 (s, 1H), 3.74 (s, 2H), 2.49-2.36(m, 4H), 1.69-1.50 (m, 10H), 1.48-1.40 (m, 2H), 1.39-1.19 (m, 6H),1.18-1.12 (m, 6H), 0.95-0.86 (m, 9H).

Preparation of 1-(5-Tributylstannanylthiazol-2-ylmethyl)-piperidine

To a cold (−78° C.) solution of 1-thiazol-2-ylmethylpiperidine (2.73 g,15.0 mmol) anhydrous THF (100 mL) was added n-butyllithium (8.95 mL,16.5 mmol). After 30 minutes, a solution of tributyltin chloride (4.93mL, 18.2 mmol) in anhydrous THF (40 mL) was to the reaction mixture.After 10 minutes, the solution was allowed to warm to ambienttempertaure and saturated aqueous sodium hydrogen carbonate was added.The aqueous phase was extracted with tert-butylmethyl ether (3×50 mL).The combined organic phase was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford a colourless oil that wasthen purified by flash chromatography (silica, 12 g column, ISCO, 0-40%ethyl acetate in cyclohexane) to afford the title compound as acolourless oil (5.1 g, 72%). ¹H NMR (CDCl₃, 400 MHz): 7.62 (t, J=6.4 Hz,1H), 3.88 (s, 2H), 2.54-2.47 (m, 4H), 1.69-1.49 (m, 10H), 1.50-1.40 (m,2H), 1.40-1.26 (m, 6H), 1.15-1.08 (m, 6H), 0.95-0.85 (m, 9H).

Preparation of5-Ethyl-2-tributylstannanyl-4,5,6,7-tetrahydro-thiazolo[4,5c]pyridine

To a cold (−78° C.) solution of5-ethyl-4,5,6,7-tetrahydrothiazolo-[4,5-c]pyridine (262 g, 1.56 mmol)anhydrous THF (10 mL) was added n-butyllithium (2.5M in hexanes, 0.68mL, 1.72 mmol). After 30 minutes, a solution of tributyltin chloride(0.51 mL, 1.87 mmol) in anhydrous THF (5 mL) was to the reactionmixture. After 10 minutes, the solution was allowed to warm to ambienttemperature and saturated aqueous sodium hydrogen carbonate was added.The aqueous phase was extracted with ethyl acetate (50 mL), dried overanhydrous sodium sulfate, filtered and evaporated in vacuo to afford acolourless oil (450 mg, quantitative yield) that was used in the nextstep without purification. ¹H NMR (CDCl₃, 300 MHz): 3.78 (m, 1H),2.96-2.88 (m, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.64 (q, J=7.2 Hz, 2H),1.62-1.49 (m, 6H), 1.36-1.12 (m, 12H), 0.94-0.82 (m, 12H).

Preparation of 1-Methyl-5-(trimethylstannyl)-1H-1,2,3-triazole

To a stirred solution of 1-methyl-1H-1,2,3-triazole (0.5 g, 6.0 mmol) inanhydrous tetrahydrofuran (50 mL) at −78° C. under an atmosphere ofnitrogen was added n-butyllithium (2.5M solution in hexanes, 2.6 mL, 6.6mmol) dropwise over ten minutes. On complete addition the reaction wasallowed to warm to −30° C. and stirred for 2 h. A solution ofchlorotrimethylstannane (1.3 g, 6.6 mmol) in tetrahydrofuran (2 mL) wasadded dropwise over 10 minutes then the reaction mixture was allowed towarm to room temperature over 2 h. The reaction was quenched by theaddition of saturated ammonium chloride solution (5 mL) then dilutedwith water (20 mL). The solvent was evaporated in vacuo and the aqueousphase extracted with ethyl acetate (2×30 mL). The combined organic layerwas dried over sodium sulfate, filtered and concentrated to afford apale yellow oil (1.4 g, 90%). ¹H NMR (DMSO-D₆,400 MHz): 7.61 (s, 1H),4.04 (s, 3H), 0.40 (s, 9H).

Preparation of1-Benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)-1H-1,2,3-triazole

Step 1:1-Benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-iodo-1H-1,2,3-triazole

A mixture of tert-butyldimethyl(prop-2-ynyloxy)silane (1.2 mL, 5.9mmol), (azidomethyl)benzene (0.81 mL, 6.5 mmol), N-bromosuccinimide(1.25 g, 7.0 mmol), copper (I) iodide (1.23 g, 6.5 mmol) andN,N-diisopropylethylamine (1.0 mL, 5.9 mmol) in tetrahydrofuran (48 mL)was stirred at room temperature for 3 h. The mixture was concentrated invacuo and the resultant residue was dissolved in ethyl acetate (75 mL)and washed with water (50 mL). The layers were separated, the organiclayer was dried over anhydrous sodium sulfate, filtered and evaporatedto afford a residue that was purified by flash chromotagraphy (silica,40 g column, ISCO, 0-25% ethyl acetate in heptane) to afford the titlecompound as a white solid (970 mg, 40%). ¹H NMR (DMSO-D₆, 400 MHz,) δ7.34 (m, 3H), 7.18 (m, 2H), 5.63 (s, 2H), 4.65 (s, 2H), 0.85 (s, 9H),0.07 (s, 6H).

Step 2:1-Benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)-1H-1,2,3-triazole

A degassed mixture of1-benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-iodo-1H-1,2,3-triazole(450 mg, 1.0 mmol), bis(triphenylphosphine) palladium(II) dichloride (37mg, 0.05 mmol), hexamethylditin (0.65 mL, 3.1 mmol) andN,N-diisopropylethylamine (0.36 mL, 2.1 mmol) in 1,4-dioxane (8 mL) washeated at 105° C. for 2 h. The reaction mixture was quenched with water(1 mL) and concentrated to afford a residue that was purified by flashchromotagraphy (silica, 40 g column, ISCO, 0-25% ethyl acetate inheptane) to afford the title compound as a yellow oil (270 mg, 55%). ¹HNMR (DMSO-D₆, 400 MHz,): 7.31 (m, 3H), 6.94 (m, 2H), 5.62 (s, 2H), 4.72(s, 2H), 0.83 (s, 9H), 0.20 (s, 9H), 0.03 (s, 6H).

Preparation of 1-Isopropyl-4-tributylstannanyl-1H-pyrazole

n-Butyllithium (2.5M in hexanes, 1.38 mL, 3.45 mmol) was added over 15min to a solution of 4-bromo-1-isopropyl-1H-pyrazole (500 mg, 2.65 mmol)in diethyl ether (10 mL) at −78° C. After 30 min, a solution oftri-n-butylstannane chloride (920 μL, 3.45 mmol) in diethyl ether (1 mL)was added and the resultant reaction mixture was left to stir at −78° C.for 1 h, then allowed to warm to ambient temperature. The reactionmixture was diluted with diethyl ether (40 mL) and washed with water (20mL), then brine (20 mL). The organic layer was separated, dried oversodium sulfate, filtered and evaporated in vacuo to afford the titleproduct as a colourless oil (98 mg, 94%) which was used without furtherpurification. ¹H NMR (CDCl₃, 400 MHz): 7.46-7.42 (m, 1H); 7.28 (t, J=4.2Hz, 1H); 4.59-4.43 (m, 1H); 1.58-1.42 (m, 12H); 1.39-1.24 (m, 6H);1.02-0.77 (m, 15H).

Preparation of 7-(4-Bromobenzyl)-2-oxa-7-aza-spiro[3.5]nonane

A mixture of 4-bromobenzyl bromide (0.26 g, 1.04 mmol), triethylamine(0.21 mL, 2.07 mmol) and 2-oxa-7-azaspiro[3.5]nonane (0.50 g, 2.07 mmol)in THF (20 mL) was heated under reflux for 5 h. The reaction mixture wascooled to ambient temperature, the solid removed by filtration and thefiltrate was concentrated under reduced pressure. The resultant residuewas loaded onto an SCX-2 cartridge (10 g) and eluted with 2N ammonia inMeOH to afford the title compound (0.30 g, 97%). ¹H NMR (CDCl₃, 300MHz): 7.47-7.41 (m, 2H), 7.19 (d, J=8.1 Hz, 2H), 4.40 (s, 4H), 3.45-3.40(m, 2H), 2.38-2.28 (s, 2H), 1.92-1.86 (s, 4H). LCMS (Method B):R_(T)=1.89 min, M+H⁺=296/298.

Preparation of 2-(4-Bromobenzyl)-2-aza-bicyclo[2.2.1]heptane

A stirred solution of 4-bromobenzyl bromide (66 mg, 0.26 mmol),triethylamine (0.22 mL, 1.56 mmol) and 2-azabicyclo[2.2.1]heptane (71mg, 0.52 mmol) in THF (10 mL) was heated under reflux for 5 h. Thereaction mixture was cooled to ambient temperature, the solid removed byfiltration and the filtrate concentrated under reduced pressure toafford the title compound (70 mg, quantitiative yield) that was used inthe next step without further purification. LCMS (Method B): R_(T)=2.04min, M+H⁺=266/268.

Preparation of 2-Bromo-6-ethyl-4,5,6,7-tetrahydrothieno[2,3c]pyridine

Step 1: 2-Bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine hydrobromide

A solution of bromine (139 mg, 0.87 mmol) in acetic acid (0.5 mL) wasadded to a solution of 4,5,6,7-tetrahydrothieno[2,3-c]pyridinehydrochloride (150 mg, 0.85 mmol) in acetic acid (3 mL) and the mixtureleft to stir at ambient temperature for 1.5 h. The resultant precipitatewas collected by filtration, washed with diethyl ether and left to airdry to afford the title compound as an off-white solid (230 mg, 90%). ¹HNMR (DMSO-D₆, 300 MHz): 9.19 (s, 2H), 7.09 (s, 1H), 4.29-4.26 (m, 2H),2.86-2.78 (m, 2H), 2.52-2.48 (m, 2H). LCMS (Method B): R_(T)=1.65 min,M+H⁺=218/220.

Step 2: 2-Bromo-6-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine

Sodium borohydride (146 mg, 3.85 mmol) was added to cooled (0° C.) asuspension of 2-bromo-4,5,6,7-tetrahydrothieno[2,3-c]pyridinehydrobromide (230 mg, 0.77 mmol) in acetic acid (1.5 mL) andtetrahydrofuran (2.8 mL). On complete addition the mixture was heated to60° C. for 3 h. The mixture was allowed to cool to ambient temperaturethen partitioned between ethyl acetate and water. The pH of the aqueousphase was adjusted to 10 by the addition of 3N sodium hydroxide solutionand the layers separated. The organic layer was washed with brine, driedover anhydrous sodium sulfate and evaporated to give the title compoundas a yellow oil (181 mg, 96%). ¹H NMR (DMSO-D₆, 300 MHz): 6.93 (s, 1H),3.50-3.47 (m, 2H), 3.66-2.46 (m, 6H), 1.05 (t, J=7.2 Hz, 3H). LCMS(Method B): R_(T)=1.79 min, M+H⁺=246/248.

Preparation of Trifluoromethanesulfonic acid2-ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl ester

Step 1: 2-Ethyl-6,8-dimethoxy-3,4-dihydroisoquinolinium iodide

Ethyl iodide (0.6 mL, 7.32 mmol) was added to a solution of6,8-dimethoxy-3,4-dihydroisoquinoline (700 mg, 3.66 mmol) inacetonitrile (15 mL) and the mixture was left to stir in the dark for 20h. The resultant precipitate was collected by filtration, washed withacetonitrile and left to air dry to afford the title compound as ayellow solid (750 mg, 95%). ¹H NMR (CD₃OD, 300 MHz): 8.96 (s, 1H), 6.63(d, J=2.2 Hz, 1H), 6.61 (d, J=2.2 Hz, 1H), 4.02-3.88 (m, 7H), 3.18 (t,J=7.9 Hz, 2H), 2.03 (s, 5H), 1.47 (t, J=7.3 Hz, 3H).

Step 2: 2-Ethyl-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline

Sodium borohydride (260 mg, 6.86 mmol) was added to a cooled (0° C.)solution of 2-ethyl-6,8-dimethoxy-3,4-dihydroisoquinolinium iodide (1.19g, 3.43 mmol) in methanol (15 mL). On complete addition the mixture wasallowed to warm to ambient temperature and stirred for 1.5 h. Themixture was evaporated in vacuo and the resultant residue waspartitioned between diethyl ether and water. The organic phase was driedover sodium sulfate, filtered and evaporated to afford the titlecompound as a yellow oil (741 mg, 98%). ¹H NMR (CDCl₃, 300 MHz): 6.27(d, J=2.3 Hz, 1H), 6.24 (d, J=2.3 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H),3.51-3.47 (m, 2H), 2.89-2.83 (m, 2H), 2.71-2.64 (m, 2H), 2.60 (q, J=7.2Hz, 2H), 1.19 (t, J=7.2 Hz, 3H). LCMS (Method B): R_(T)=1.62 min,M+H⁺=222.

Step 3: 2-Ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol

A mixture of 2-ethyl-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline (280mg, 1.27 mmol) in 48% aqueous hydrobromic acid (3 mL) was heated at 65°C. for 24 h. The mixture was added to saturated sodium hydrogencarbonate solution and extracted with ethyl acetate (3×50 mL). Thecombined organic phase was washed with water, dried over anhydroussodium sulfate, filtered and evaporated in vacuo. The resultant solidwas purified by flash chromatography (silica, 12 g column, ISCO, 0-20%(2N ammonia in MeOH) in DCM) to afford the title compound as an offwhite solid (153 mg, 58%). ¹H NMR (CDCl₃, 300 MHz): 6.11 (d, J=2.2 Hz,1H), 5.93 (d, J=2.2 Hz, 1H), 3.67 (s, 3H), 3.55-3.49 (m, 2H), 2.72-2.58(m, 6H), 1.21 (t, J=7.2 Hz, 3H). LCMS (Method B): R_(T)=1.58 min,M+H⁺=208.

Step 4: Trifluoromethanesulfonic acid2-ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl ester

Triflic anhydride (0.54 mL, 3.2 mmol) was added dropwise over 15 minutesto a suspension of 2-ethyl-8-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol(328 mg, 1.6 mmol) in pyridine (0.52 mL, 6.4 mmol) and DCM (15 mL). Thereaction mixture was allowed to warm to ambient temperature and stirredfor 2 h. The mixture was diluted with DCM (60 mL), washed with water(100 mL), dried over sodium sulfate, filtered and evaporated in vacuo.The resultant solid was purified by flash chromatography (silica, 12 gcolumn, ISCO, 0-100% ethyl acetate in pentane) to afford the titlecompound as a yellow solid (341 mg, 63%). ¹H NMR (CDCl₃, 300 MHz): 6.76(d, J=2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 4.30-4.10 (m, 2H), 3.87 (s,3H), 3.50-3.37 (m, 2H), 3.36-3.10 (s, 4H), 1.51 (t, J=7.2 Hz, 3H). LCMS(Method B): R_(T)=2.39 min, M+H⁺=340.

Preparation of 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole

A mixture of 5-bromothiazole (0.54 mL, 6.1 mmol), bis(pinacolato)diboron(1.56 g, 6.1 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250 mg, 0.3mmol), and potassium acetate (1.8 g, 18.3 mmol) in 1,4-dioxane (20 mL)was heated at 100° C. for 12 h. The cooled reaction mixture was dilutedwith DCM (50 mL) and washed with water (15 mL). The organic phase wasseparated, dried over sodium sulfate, filtered and evaporated in vacuo.The resultant residue was purified by flash chromatography through athin pad of silica eluting with DCM to afford the title compound as abrown solid which was used without further purification.

Preparation of 2-Methyl-5-(trimethylstannyl)thiazole

To a cooled (−78° C.) solution of 2-methylthiazole (1.0 g, 10 mmol) inanhydrous diethyl ether (20 mL) under an atmosphere of nitrogen wasadded n-butyllithium (2.5M solution in hexanes, 5.2 mL, 13 mmol)dropwise over 10 minutes. The reaction mixture was stirred for 1 h andthen allowed to warm to 0° C. and stirred for 1 h. The reaction mixturewas then cooled to −78° C. and a solution of chlorotrimethylstannane(1.8 g, 9.0 mmol) in anhydrous diethyl ether (10 mL) was added dropwiseover 10 minutes. The reaction mixture was stirred for 30 minutes andthen allowed to warm to room temperature and stirred for 16 h. Thereaction was quenched with water (20 mL) and extracted with ethylacetate (2×50 mL). The combined organic layer was dried over sodiumsulfate, filtered, and evaporated in vacuo to afford the title compoundas a yellow oil which was used without any further purification.

Preparation of 1,2-Dimethyl-5-(tributylstannyl)-1H-imidazole

The title compound was prepared following a similar procedure toprevious example using 5-bromo-1,2-dimethyl-1H-imidazole andtributylchlorostannane.

Preparation of 3-(Trimethylstannyl)imidazo[1,2-a]pyrimidine

To a cooled (−78° C.) solution of 3-bromoimidazo[1,2-a]pyrimidine (1.0g, 5.1 mmol) in anhydrous tetrahydrofuran (40 mL) under an atmosphere ofnitrogen was added isopropylmagnesium chloride (2.0M solution intetrahydrofuran, 2.8 mL, 5.6 mmol) dropwise over 10 minutes. Thereaction was stirred for 2 h then a solution of chlorotrimethylstannane(1.1 g, 5.6 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10minutes. The reaction mixture was stirred for 30 minutes then allowed towarm to room temperature. The reaction was quenched with water (20 mL)and extracted with DCM (2×50 mL). The combined organic layer was driedover sodium sulfate, filtered, and evaporated in vacuo to afford thetitle compound as an orange oil which was used without any furtherpurification.

Compounds of the Examples in Table 1 were made via procedures describedabove using appropriate starting materials, reagents and general Suzukiconditions.

TABLE 1 Boronic acid/ LCMS ester Final R_(T), prepa- Cou- puri- M + Ex-ration pling fication H⁺, am- general Meth- Meth- Meth- pleStructure/Name Method od od(s) od ¹H NMR (ppm) 1

  3-[4-(1-Methyl-piperidin-4-yl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B A E² 5.8, 368, A (DMSO-D₆, 300 MHz): 12.87(br s, 1H), 9.05-9.02 (m, 2H), 8.99 (d, J = 2.3 Hz, 1H), 8.93 (d, J =1.0 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H),2.94-2.84 (m, 2H), 2.54-2.47 (m, 1H), 2.21 (s, 3H), 2.04-1.94 (m, 2H),1.82-1.66 (m, 4H). 2

  4-[3-(6-Cyano-9H-dipyrido[2,3- b;4′,3′-d]pyrrol-3-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester A A G 11.6, 455, A(DMSO-D₆, 300 MHz): 9.02-8.95 (m, 3H), 8.85 (s, 1H), 7.41-7.32 (m, 2H),7.24 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 3.51 (m, 4H), 3.24(m, 4H), 1.44 (s, 9H). 3

  3-(4-Pyrrolidin-1-yl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A A none 11.7, 340, A (DMSO-D₆, 400 MHz): 12.78 (br. s,1H), 9.01 (d, J = 1.0 Hz, 1H), 8.95-8.91 (m, 3H), 7.63 (d, J = 8.5 Hz,2H), 6.69 (d, J = 8.5 Hz, 2H), 3.33-3.25 (m, 4H), 2.01-1.95 (m, 4H). 4

  N-{2-[4-(6-Cyano-9H-dipyrido [2,3-b;4′,3′-d]pyrrol-3-yl)-phenoxy]-ethyl}- methanesulfonamide A A B 8.4, 408, A (DMSO-D₆, 400MHz): 12.85 (s, 1H), 9.05-9.00 (m, 2H), 8.98 (d, J = 2.3 Hz, 1H),8.94-8.91 (m, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.31 (t, J = 5.9 Hz, 1H),7.14 (d, J = 8.3 Hz, 2H), 4.12 (t, J = 5.6 Hz, 2H), 3.41- 3.35 (m, 2H),2.98 (s, 3H). 5

  3-[4-(1-Methyl-piperidin-4- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile A A E³ 6.24, 382, A(DMSO-D₆, 300 MHz): 9.06 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.0 Hz, 1H),9.01 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.0 Hz, 1H), 7.72 (d, J = 7.9 Hz,2H), 7.34 (d, J = 7.9 Hz, 2H), 2.73 (d, J = 10.7 Hz, 2H), 2.57 (d, J =6.6 Hz, 2H), 2.12 (s, 3H), 1.80 (t, J = 5.8 Hz, 2H), 1.60-1.40 (m, 3H),1.30-1.10 (m, 2H). 6

  3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile C A B 5.83, 368, A(DMSO-D₆, 300 MHz): 9.09-9.01 (m, 3H), 8.95 (d, J = 1.0 Hz, 1H), 7.76(d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 3.50 (s, 2H), 2.37 (m,4H), 1.55-1.48 (m, 4H), 1.41 (m, 2H). 7

  3-(4-Morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile C A H¹ 5.43, 370, A(DMSO-D₆, 300 MHz): 9.09-9.01 (m, 3H), 8.94 (d, J = 1.1 Hz, 1H), 7.78(d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 3.60 (m, 4H), 3.54 (s,2H), 2.40 (m, 4H). 8

  3-[4-(4-Benzyl-morpholin-2-yl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A A A³ 6.77, 446, A (DMSO-D₆, 400 MHz): 12.90(br. s, 1H), 9.10 (d, J = 2.3 Hz, 1H), 9.07 (d, J = 1.1 Hz, 1H), 9.00(d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H),7.50 (d, J = 8.2 Hz, 2H), 7.35-7.30 (m, 4H), 7.29-7.24 (m, 1H), 4.59(dd, J = 10.1, 2.3 Hz, 1H), 3.98-3.93 (m, 1H), 3.72 (td, J = 11.4, 2.4Hz, 1H), 3.56 (d, J = 13.0 Hz, 1H), 3.53 (d, J = 13.0 Hz, 1H), 2.91 (d,J = 11.5 Hz, 1H), 2.72 (d, J = 11.5 Hz, 1H), 2.20 (td, J = 11.5, 3.3 Hz,1H), 2.08-2.01 (m, 1H). 9

  3-(3-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile C A B¹ 5.94, 368, A(CDCl₃, 300 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H),8.70 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 1.0 Hz, 1H) 7.66 (s, 1 H), 7.57(d, J = 7.1 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.39 (d, J = 7.1 Hz, 1H),3.60 (s, 2H), 2.47 (m, 4H), 1.63 (m, 4H), 1.48 (m, 2H). 10

  3-(3-Morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile C A B¹ 5.59, 370, A(CDCl₃, 300 MHz): 9.03 (s, 1H), 8.90 (s, 1H), 8.69 (s, 1H), 8.48 (s,1H), 7.66 (s, 1H), 7.58 (m, 1H), 7.52 (br. t, J = 7.8 Hz, 1H), 7.43 (m,1H), 3.76 (m, 4H), 3.63 (s, 2H), 2.54 (m, 4H). 11

  4-[4-(6-Cyano-9H-dipyrido[2,3- b;4′,3′-d]pyrrol-3-yl)-benzyl)-piperazine-1- carboxylic acid tert-butyl ester A A B¹ 6.75, 469, A(CDCl₃, 300 MHz): 9.02 (d, J = 1.1 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H);8.68 (d, J = 2.2 Hz, 1H); 8.48 (d, J = 1.1 Hz, 1H); 7.65 (br d, J = 7.9Hz, 2H); 7.50 (br d, J = 7.9 Hz, 2H); 3.62 (s, 2H); 3.55-3.44 (m, 4H);2.47 (m, 4H); 1.46 (s, 9H) 12

  3-[4-(4-Ethyl-piperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile A A B¹ 5.83, 383, A(DMSO-D₆, 400 MHz): 12.76 (s, 1H); 9.00-8.86 (m, 4H); 7.62 (d, J = 8.4Hz, 2H); 7.05 (d, J = 8.4 Hz, 2H); 3.18 (m, 4H); 2.48 (m, 4H); 2.34 (q,J = 7.2 Hz, 2H); 1.00 (t, J = 7.2 Hz, 3H). 13

  3-[4-((2S,6R)-2,6-Dimethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile BA B 6.26, 396, A (DMSO-D₆, 300 MHz): 9.05 (d, J = 2.3 Hz, 1H), 9.04 (d,J = 1.1 Hz, 1H), 9.00 (d, J = 2.3 Hz, 1H), 8.93 (d, J = 1.1 Hz, 1H),7.72 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 3.78 (s, 2H),2.55-2.42 (m, 2H), 1.66-1.52 (m, 3H), 1.37-1.20 (m, 3H), 1.00 (d, J =6.2 Hz, 6H).

Compounds of the Examples in Table 2 were prepared via proceduresdescribed above using appropriate starting materials, reagents andgeneral Suzuki conditions.

TABLE 2 LCMS Boronic Final R_(T), acid/ Cou- puri- M + Ex- ester plingDepro- fication H⁺, am- general Meth- tection Meth- Meth- pleStructure/Name Method od Method od(s) od ¹H NMR (ppm) 14

  3-(3-Piperazin-1-yl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile From Example 1 N/A A G¹ 5.81, 355, A (DMSO-D₆, 300 MHz):12.99 (s, 1H), 9.30 (s, 2H), 9.11 (d, J = 2.2 Hz, 1H), 9.06-9.01 (m,2H), 8.95 (s, 1H), 7.47-7.39 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H),7.09-7.03 (m, 1H), 3.53 (m, 4H), 3.26 (s, 4H). 15

  3-(4-Morpholin-4-yl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile NA D A G¹ 9.1, 356, A (DMSO-D₆, 400 MHz): 12.88 (s, 1H),9.04-9.02 (m, 2H), 8.98 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.0 Hz, 1H),7.72 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 3.81 (t, J = 4.6 Hz,4H), 3.24 (t, J = 4.6 Hz, 4H). 16

  3-[3-(1-Methyl-piperidin-4-yl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D A F 6.1, 368, A (DMSO-D₆, 400 MHz): 12.96 (s,1H), 10.35 (s, 1H), 9.09 (d, J = 2.2 Hz, 1H), 9.06 (d, J = 1.0 Hz, 1H),9.02 (d, J = 2.2 Hz, 1H), 8.95 (s, 1H), 7.72- 7.65 (m, 2H), 7.53 (t, J =7.6 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 3.53 (d, J = 12.0 Hz, 2H),3.16-3.06 (m, 2H), 2.95-2.90 (m, 1H), 2.80 (d, J = 4.6 Hz, 3H),2.13-2.04 (m, 4H). 17

  3-[4-((S)-Pyrrolidin-3-yloxy)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A D B C, E 5.64, 356, A (DMSO-D₆, 400 MHz):8.99-8.93 (m, 2H), 8.92 (d, J = 2.3 Hz, 1H), 8.87 (d, J = 1.1 Hz, 1H),7.67 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 4.92- 4.85 (m, 1H),3.14-2.99 (m, 1H), 2.94-2.71 (m, 3H), 2.06-1.95 (m, 1H), 1.80-1.72 (m,1H). 18

  3-[4-((R)-Pyrrolidin-3-yloxy)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A D B C, E 5.64, 356, A (DMSO-D₆, 300 MHz): 9.03(d, J = 1.0 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.97 (d, J = 2.3 Hz, 1H),8.92 (d, J = 1.1 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.5 Hz,2H), 4.98-4.90 (m, 1H), 3.15- 3.08 (m, 1H), 2.97-2.81 (m, 3H), 2.08-2.02(m, 1H), 1.85-1.75 (m, 1H). 19

  3-[4-(Piperidin-3-yloxy)-phenyl]- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A D B C, E 5.85, 370, A (DMSO-D₆, 300 MHz): 9.02 (d, J =1.1 Hz, 1H), 9.00 (d, J = 2.3 Hz, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.92(d, J = 1.1 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H),4.37-4.29 (m, 1H), 3.19- 3.09 (m, 1H), 2.84-2.73 (m, 1H), 2.59-2.44 (m,2H), 2.12-2.02 (m, 1H), 1.75-1.63 (m, 1H), 1.57- 1.43 (m, 2H). 20

  3-[4-(4-Hydroxy-1-methyl-piperidin- 4-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D A A 5.3, 384, A (DMSO-D₆, 300 MHz):12.80 (br. s, 1H), 9.08 (d, J = 2.3 Hz, 1H), 9.05 (d, J = 1.1 Hz,1H),9.03 (d, J = 2.3 Hz, 1H),8.95 (d, J = 1.1 Hz, 1H), 7.78 (d, J = 8.3Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 4.99 (s, 1H), 2.71 (d, J = 10.4 Hz,2H), 2.57-2.46 (m, 2H), 2.32 (s, 3H), 2.13-2.01 (m, 2H), 1.67 (d, J =13.0 Hz, 2H). 21

  3-(4-(2-Dimethylamino-ethoxy)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile NA D A A 5.6, 358, A (DMSO-D₆, 300 MHz): 12.75(br. s, 1H), 9.05- 9.02 (m, 2H), 8.99 (d, J = 2.3 Hz, 1H), 8.95 (d, J =1.1 Hz, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 4.14(t, J = 5.8 Hz, 2H), 2.68 (t, J = 5.8 Hz, 2H), 2.26 (s, 6H). 22

  3-[3-(4-Methyl-piperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile A A A B 5.86, 368, A(DMSO-D₆, 300 MHz): 9.09-8.98 (m, 3H), 8.95 (s, 1H), 7.42-7.30 (m, 2H),7.20 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 3.33 (s, 4H), 2.50(s, 4H), 2.25 (s, 3H). 23

  3-(4-Morpholin-2-yl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile From Example 8 NA C C² 5.57, 356, A (DMSO-D₆, 300 MHz):9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.02 (d, J = 2.3 Hz,1H), 8.95 (d, J = 1.1 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.50 (d, J =8.2 Hz, 2H), 4.47 (dd, J = 10.2, 2.4 Hz, 1H), 3.92 (dt, J = 10.9, 2.2Hz, 1H), 3.58- 3.69 (m, 1H), 2.99 (dd, J = 12.3, 2.5 Hz, 1H), 2.80-2.74(m, 2H), 2.59- 2.54 (m, 1H). 24

  3-[3-(1-Methyl-piperidin-4-yloxy)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D A G, E 6.15, 384, A (DMSO-D₆, 300 MHz): 12.90(s, 1H), 9.09 (d, J = 2.3 Hz, 1H), 9.04 (s, 1H), 9.02 (d, J = 2.3 Hz,1H), 8.95 (s, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.40- 7.32 (m, 2H), 7.02(d, J = 8.1 Hz, 1H), 4.63-4.43 (m, 1H), 2.69-2.59 (m, 2H), 2.30-2.13 (m,5H), 2.05-1.93 (m, 2H), 1.75- 1.64 (m, 2H). 25

  3-[1-(2-Pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-9H-dipyrido[2,3-b;4′,3′- d]pyrrole-6-carbonitrile D D A E,K 5.07, 358, A (DMSO-D₆, 400 MHz): 12.88 (s, 1H), 10.93 (s, 1H), 9.02(d, J = 1.0 Hz, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.97 (d, J = 2.2 Hz, 1H),8.85 (d, J = 1.0 Hz, 1H), 8.42 (s, 1H), 8.12 (s, 1H), 4.65 (t, J = 6.3Hz, 2H), 3.70 (q, J = 6.0 Hz, 2H), 3.57-3.46 (m, 2H), 3.02-2.94 (m, 2H),2.04-1.93 (m, 2H), 1.91-1.82 (m, 2H). 26

  3-[4-(1-Methyl-piperidin-4-yloxy)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D A G, E 6.05, 384, A (DMSO-D₆, 400 MHz): 12.82(s, 1H), 9.03 (d, J = 1.1 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.97 (d, J= 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.12(d, J = 8.5 Hz, 2H), 4.49-4.42 (m, 1H), 2.68-2.60 (m, 2H), 2.27-2.15 (m,5H), 2.02-1.93 (m, 2H), 1.73- 1.63 (m, 2H). 27

  3-(4-Piperazin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile C A B B¹, F^(1,2,5)4.92, 369, A (DMSO-D₆, 400 MHz): 12.54 (br. s, 1H), 9.03 (m, 1H), 8.99(d, J = 2.2 Hz, 1H), 8.97 (d, J = 2.2 Hz, 1H), 8.83 (m, 1H), 7.77 (d, J= 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 3.68 (s, 2H), 3.14 (t, J = 5.1Hz, 4H), 2.69 (t, J = 5.1 Hz, 4H). 28

  3-(3,5-Dimethoxy-4-piperidin-1- ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile NA A A E 6.42, 428, A (DMSO-D₅, 300MHz): 9.13 (d, J = 2.3 Hz, 1H), 9.11 (d, J = 2.3 Hz, 1H), 9.04 (d, J =1.0 Hz, 1H), 8.94 (d, J = 1.0 Hz, 1H), 7.05 (s, 2H), 3.90 (s, 6H), 3.50(s, 2H), 2.41- 2.36 (m, 4H), 1.49-1.40 (m, 4H), 1.29-1.38 (m, 2H). 29

  3-[4-(4-Methoxy-piperidin-4-yl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D B D 5.99, 384, A (DMSO-D₆, 400 MHz): 9.12 (d,J = 2.0 Hz, 1H), 9.07-9.05 (m, 2H), 8.95 (d, J = 1.0 Hz, 1H), 7.88 (d, J= 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 3.30- 3.23 (m, 2H), 3.20-3.07(m, 2H), 2.97 (s, 3H), 2.30-2.20 (m, 2H), 2.15- 2.05 (m, 2H). 30

  3-[4-(3-Hydroxy-piperidin-3-yl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D B D 5.51, 370, A (DMSO-D₆, 400 MHz): 9.06 (d,J = 2.5 Hz, 1H), 9.04 (d, J = 1.0 Hz, 1H), 9.01 (d, J = 2.5 Hz, 1H),8.93 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz,2H), 2.98-2.88 (m, 1H), 2.88- 2.81 (m, 1H), 2.70-2.64 (m, 1H), 2.61-2.52(m, 1H), 2.02-1.95 (m, 1H), 1.86-1.80 (m, 1H), 1.78- 1.70 (m, 1H),1.49-1.41 (m, 1H). 31

  3-[3-(3-Hydroxy-piperidin-3-yl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D B D 5.77, 370, A (DMSO-D₆, 400 MHz): 9.09 (d,J = 2.0 Hz, 1H), 9.05 (d, J = 1.0 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H),8.99 (d, J = 1.0 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.58(d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 2.98-2.91 (m, 2H),2.76-2.68 (m, 1H), 2.67-2.53 (m, 1H), 2.07 (td, J = 8.5, 4.0 Hz, 1H),1.90-1.85 (m, 1H), 1.81-1.73 (m, 1H), 1.51- 1.44 (m, 1H). 32

  3-[4-(3-Hydroxy-1-methyl-piperidin- 3-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D B B 5.58, 384, A (DMSO-D₆, 400MHz): 9.11 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 1.0 Hz, 1H), 9.05 (d, J =2.0 Hz, 1H), 8.95 (d, J = 1.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.70(d, J = 8.0 Hz, 2H), 3.27-3.22 (m, 2H), 3.17- 3.16 (m, 1H), 3.09-2.97(m, 1H), 2.75 (s, 3H), 2.20-1.99 (m, 2H), 1.88- 1.81 (m, 2H). 33

  3-[4-(4-Fluoro-piperidin-4-yl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D B B 6.15, 372, A (DMSO-D₆, 400 MHz): 9.11 (d,J = 2.0 Hz, 1H), 9.06 (d, J = 1.0 Hz, 1H), 9.04 (d, J = 2.0 Hz, 1H),8.95 (d, J = 1.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz,2H), 3.14-2.95 (m, 2H), 3.03- 2.95 (m, 2H), 2.26-2.13 (m, 2H), 2.10-1.95(m, 2H). 34

  3-[4-(3,3-Dimethyl-pyrrolidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C A — B 6.32, 382, A (DMSO-D₆, 400MHz): 12.89 (br s, 1H), 9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz,1H), 9.02 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.76 (d, J =8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 2.60 (t, J = 7.0Hz, 2H), 2.29 (s, 2H), 1.55 (t, J = 7.0 Hz, 2H), 1.07 (s, 6H). 35

  3-[4-(3,3-Difluoro-pyrrolidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C D — B, S 6.44, 390, A (DMSO-D₆,300 MHz): 12.89 (s, 1H), 9.09 (d, J = 2.3 Hz, 1H), 9.05 (d, J = 1.0 Hz,1H), 9.03 (d, J = 2.2 Hz, 1H), 8.95 (d, J = 1.0 Hz, 1H), 7.79 (d, J =8.0 Hz, 2H), 7.49 (d, J = 7.99 Hz, 2H), 3.70 (s, 2H), 2.91 (t, J = 13.3Hz, 2H), 2.77-2.70 (m, 2H), 2.34-2.21 (m, 2H). 36

  3-[4-(3-Trifluoromethyl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C* D — B⁸ 6.67, 436, A (DMSO-D₆,400 MHz): 12.91 (s, 1H), 9.09 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz,1H), 9.03 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.78 (d, J =8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 3.61 (s, 2H), 3.03-2.95 (m, 1H),2.87-2.79 (m, 1H), 2.03- 1.93 (m, 2H), 1.92-1.83 (m, 1H), 1.76-1.67 (m,1H), 1.60-1.47 (m, 1H), 1.32-1.18 (m, 1H). 37

  3-[4-(3-Fluoro-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile C* D — B 5.76,386, A (DMSO-D₆, 400 MHz): 12.91 (s, 1H), 9.09 (d, J = 2.3 Hz, 1H), 9.05(d, J = 1.1 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H),7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.74-4.57 (m, 1H),3.59 (s, 2H), 2.78-2.64 (m, 1H), 2.49- 2.36 (m, 2H), 2.35-2.24 (m, 1H),1.91-1.65 (m, 2H), 1.62-1.41 (m, 2H). 38

  3-(3-Piperidin-1-ylmethyl-isothiazol- 5-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile monoformate Stille B — D 5.70, 375, A (CDCl₃ plusCD₃OD, 400 MHz): 9.03 (d, J = 1.0 Hz, 1H), 8.97 (d, J = 2.2 Hz, 1H),8.92 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 1.1 Hz, 1H), 8.42 (s, 1H), 4.12(s, 2H), 2.99-2.86 (m, 4H), 1.85-1.74 (m, 4H), 1.66-1.55 (m, 2H). 39

  3-(2-Piperidin-1-ylmethyl- thiazol-5-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile Stille B — ⁵ 5.55, 375, A (DMSO-D₆, 400MHz): 9.06-9.02 (m, 3H), 8.94 (d, J = 1.0 Hz, 1H), 8.18 (s, 1H), 3.81(s, 2H), 2.56-2.49 (m, 4H), 1.62- 1.52 (m, 4H), 1.49-1.38 (m, 2H). 40

  3-(5-Ethyl-4,5,6,7-tetrahydro-thiazolo[4,5-c]pyridin-2-yl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileStille B — B⁴ 5.62, 360, A (DMSO-D₆, 400 MHz): 12.90 (s, 1H), 9.02 (d, J= 1.1 Hz, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.95 (d, J = 1.1 Hz, 1H), 8.93(d, J = 2.3 Hz, 1H), 7.32 (s, 1H), 3.63 (s, 2H), 2.77- 2.65 (m, 4H),2.57 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). *no sodium iodideused in this reaction

The compounds of the Examples in Table 3 were prepared via generalSuzuki procedures described above, employing commercially availableboronic acids.

TABLE 3 LCMS Ex- Cou- Depro- R_(T), M + am- pling tection PurificationH⁺, ple Structure/Name Method Method Method(s) Method ¹H NMR (ppm) 41

  3-(1,2,3,6-Tetrahydro-pyridin-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile E A E, H 4.38, 276, A(DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.35 (s, 2H), 9.04 (d, J = 1.0 Hz,1H), 8.93 (d, J = 1.0 Hz, 1H), 8.91 (d, J = 2.3 Hz, 1H), 8.88 (d, J =2.3 Hz, 1H), 6.36 (s, 1H), 3.82 (s, 2H), 3.42-3.35 (s, 2H), 2.89-2.81(s, 2H). 42

  3-(3,5-Dimethoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D A G², J 10.0, 331, A (DMSO-D₆, 400 MHz): 12.91 (s, 1H),9.11 (d, J = 2.3 Hz, 1H), 9.05- 9.03 (m, 2H), 8.93 (d, J = 1.0 Hz, 1H),6.96 (d, J = 2.2 Hz, 2H), 6.57 (t, J = 2.2 Hz, 1H), 3.85 (s, 6H). 43

  3-[4-Pyrrolidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile B NA B 5.69, 354, A(CD₃OD, 400 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.95 (d, J = 2.2 Hz, 1H),8.93 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 1.1 Hz, 1H), 7.82 (d, J = 8.0 Hz,2H), 7.61 (d, J = 8.0 Hz, 2H), 4.16 (s, 2H), 3.12-3.05 (m, 4H),2.06-2.01 (m, 4H). 44

  3-[4-(1-Piperidin-1-yl-ethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile B NA B 2.28, 382, A(CDCl₃, 400 MHz): 9.02 (t, J = 1.0 Hz, 1H), 8.91 (dd, J = 2.1, 0.9 Hz,1H), 8.73 (dd, J = 2.3, 1.3 Hz, 1H), 8.53 (t, J = 1.1 Hz, 1H), 7.68 (d,J = 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 3.67 (q, J = 6.7 Hz, 1H),2.68-2.50 (m, 4H), 1.73-1.63 (m, 4H), 1.56 (d, J = 6.8 Hz, 3H),1.50-1.44 (m, 2H).

Compounds of the Examples in Table 4 were made via procedures describedabove using appropriate starting materials, reagents and general SuzukiMethods.

TABLE 4 De- LCMS pro- Puri- R_(T), Cou- tec- fica- M + Ex- pling tiontion H⁺, am- Meth- Meth- Meth- Meth- ple Structure/Name od od od(s) od¹H NMR (ppm) 45

  3-[3-Methoxy-5-(1-methyl-piperidin- 4-yloxy)-phenyl]-9H-dipyrido[2,3-b; 4′,3′-d]pyrrole-6-carbonitrile F A E⁵6.4, 414, A (DMSO-D₆, 400 MHz): 12.85 (s, 1H), 9.10 (d, J = 2.3 Hz, 1H),9.04- 9.02 (m, 2H), 8.94 (d, J = 1.1 Hz, 1H), 6.95 (dt, J = 9.8, 1.8 Hz,2H), 6.57 (t, J = 2.2 Hz, 1H), 4.56-4.49 (m, 1H), 3.85 (s, 3H),2.68-2.60 (m, 2H), 2.29-2.16 (m, 5H), 2.03-1.92 (m, 2H), 1.74-1.63 (m,2H). 46

  3-(3,5-Difluoro-4-piperidin-1- ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D B 5.87, 404, A (DMSO-D₆, 300 MHz):9.19 (d, J = 2.3 Hz, 1H), 9.10 (d, J = 2.3 Hz, 1H), 9.05 (d, J = 1.1 Hz,1H), 8.87 (d, J = 1.1 Hz, 1H), 7.61 (d, J = 8.6 Hz, 2H), 3.58 (s, 2H),2.43-2.37 (m, 4H), 1.51-1.44 (m, 4H), 1.39-1.32 (m, 2H). 47

  3-[3-Bromo-5-(1-methyl-pipendin-4- yloxy-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F A G³, E 7.1, 462, A (DMSO-D₆, 400MHz): 12.85 (s, 1H), 9.14 (d, J = 2.3 Hz, 1H), 9.06- 9.04 (m, 2H), 8.93(d, J = 1.1 Hz, 1H), 7.58 (dd, J = 1.6, 1.5 Hz, 1H), 7.40 (dd, J = 2.1,1.7 Hz, 1H), 7.23 (dd, J = 2.2, 1.7 Hz, 1H), 4.63-4.56 (m, 1H),2.67-2.59 (m, 2H), 2.28- 2.15 (m, 5H), 2.02-1.91 (m, 2H), 1.74-1.64 (m,2H). 48

  3-(4,5,6,7-Tetrahydro-thieno[3,2-c] pyridin-2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G A H, B 5.33, 332, A (DMSO-D₆, 400MHz): 12.96 (s, 1H), 9.44 (br. s, 1H), 9.00 (d, J = 1.1 Hz, 1H),8.94-8.93 (m, 2H), 8.94 (d, J = 1.0 Hz, 1H), 7.39 (s, 1H), 4.20 (s, 2H),3.41 (m, 2H), 3.08 (t, J = 6.0 Hz, 2H). 49

  3-(5-Ethyl-4,5,6,7-tetrahydro- thieno[3,2-c]pyridin-2-yl)-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile G A H, B 2.17, 360, A(DMSO-D₆, 400 MHz): 13.02 (s, 1H), 10.68 (s, 1H), 9.05 (d, J = 1.0 Hz,1H), 9.00 (s, 2H), 8.99 (s, 1H), 7.42 (s, 1H), 4.51 (d, J = 15.0 Hz,1H), 4.27-4.16 (m, 1H), 3.85-3.73 (m, 1H), 3.40-3.14 (m, 5H), 1.36 (t, J= 7.2 Hz, 3H). 50

  3-(4-Piperidin-1-ylmethyl-thiophen- 2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D J^(3,5) 5.8, 374, A (DMSO-D₆, 400MHz): 12.90 (br. s, 1H), 9.05 (d, J = 2.3 Hz, 1H), 9.02 (d, J = 1.1 Hz,1H), 9.00 (d, J = 2.3 Hz, 1H), 8.96 (d, J = 1.1 Hz, 1H), 7.53 (d, J =1.4 Hz, 1H), 7.34 (d, J = 1.3 Hz, 1H), 3.45 (s, 2H), 2.40-2.33 (m, 4H),1.56-1.48 (m, 4H), 1.42- 1.37 (m, 2H). 51

  3-(4-Piperidin-1-ylmethyl-thiazol- 2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D E 5.45, 375, A (CDCl₃, 300 MHz):9.21 (d, J = 2.1 Hz, 1H), 9.05 (d, J = 2.1 Hz, 1H), 9.02 (d, J = 1.1 Hz,1H), 8.50 (d, J = 1.1 Hz, 1H), 3.79 (s, 2H), 2.63-2.55 (m, 4H),1.71-1.62 (m, 4H), 1.54- 1.46 (m, 2H). 52

  3-(4,5,6,7-Tetrahydro-thiazolo[5,4- c]pyridin-2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D E 4.66, 333, A (DMSO-D₆, 300 MHz):9.29 (s, 1H), 9.19 (s, 1H), 9.07 (s, 1H), 9.05 (s, 1H), 4.05 (s, 2H),3.14-3.07 (m, 2H), 2.85-2.79 (m, 2H). 53

  3-(4-Azetidin-1-ylmethyl-phenyl)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 5.48, 340, A (DMSO-D₆, 400 MHz): 9.07 (d, J = 2.3 Hz,1H), 9.04 (d, J = 1.1 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.94 (d, J =1.1 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 3.62(s, 2H), 3.19 (t, J = 6.9 Hz, 4H), 2.02 (p, J = 7.0 Hz, 2H). 54

  3-[4-(1-Methyl-1-piperidin-1-yl- ethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 6.24, 396, A (DMSO-D₆, 400 MHz):9.07 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.01 (d, J = 2.3 Hz,1H), 8.94 (d, J = 1.1 Hz, 1H), 7.75 (d, J = 8.1 Hz, 2H), 7.44 (d, J =8.0 Hz, 2H), 3.62 (s, 2H), 3.19 (t, J = 6.9 Hz, 4H), 2.02 (p, J = 7.0Hz, 2H). 55

  3-(3-Methoxy-4-piperidin-1- ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile K D B, G⁴ 6.29, 398, A (CDCl₃ plusCD₃OD, 300 MHz): 9.02 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.69 (d, J =2.1 Hz, 1H), 8.51 (s, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.8Hz, 1H), 7.14 (s, 1H), 3.95 (s, 3H), 3.64 (s, 2H), 2.58-2.45 (s, 4H),1.65-1.56 (m, 4H), 1.52-1.39 (m, 2H) 56

  3-(3,5-Diethyl-4-piperidin-1- ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B⁴ 2.53, 424, B (CDCl₃, 300 MHz):9.02 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.49(d, J = 1.0 Hz, 1H), 7.33 (s, 2H), 3.54 (s, 2H), 2.89 (q, J = 7.5 Hz,4H), 2.51-2.38 (m, 4H), 1.60-1.39 (m, 6H), 1.36-1.22 (m, 6H). 57

  3-(3,5-Dichloro-4-piperidin-1- ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile K D B⁴ 6.55, 436, A (CDCl₃ plus CD₃OD,300 MHz): 9.03 (s, 1H), 8.85 (s, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.48 (d,J = 0.9 Hz, 1H), 7.62 (s, 2H), 3.79 (s, 2H), 2.64- 2.52 (s, 4H),1.64-1.53 (m, 4H), 1.51-1.38 (m, 2H). 58

  3-(3-Chloro-5-methoxy-4-piperidin- 1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile K D B⁴ 6.80, 432, A (CDCl₃ plus CD₃OD,300 MHz): 8.97 (s, 1H), 8.83 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 2.2 Hz,1H), 8.46 (d, J = 1.0 Hz, 1H), 7.26 (d, J = 1.7 Hz, 1H), 6.98 (d, J =1.7 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 2H), 2.70-2.55 (m, 4H), 1.68-1.55(m, 4H), 1.51-1.37 (m, 2H). 59

  3-(3-Methoxy-5-methyl-4-piperidin- 1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile K D B⁴ 6.68, 412, A (CDCl₃, 300 MHz):8.93 (s, 1H), 8.82-8.80 (m, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.42 (s, 1H),7.02 (s, 1H), 6.91 (s, 1H), 3.84 (s, 3H), 3.50 (s, 2H), 2.48-2.34 (m,7H), 1.55- 1.43 (m, 4H), 1.43-1.31 (m, 2H). 60

  3-(3-Ethoxy-4-piperidin-1-ylmethyl- phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B⁴ 6.78, 412, A (DMSO-D₆, 400 MHz):12.94 (s, 1H), 9.12 (s, 1H), 9.07 (s, 1H), 9.05 (d, J = 1.1 Hz, 1H),8.94 (d, J = 1.0 Hz, 1H), 7.52 (s, 1H), 7.41 (m, 2H), 4.23 (d, J = 7.8Hz, 2H), 1.72- 1.50 (m, 4H), 1.49-1.33 (m, 5H). 61

  3-(3-Fluoro-4-piperidin-1-ylmethyl- phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B⁴ 6.13, 386, A (DMSO-D₆ plusTFA-D, 400 MHz): 9.22 (d, J = 2.3 Hz, 1H), 9.14 (d, J = 2.3 Hz, 1H),9.09 (d, J = 1.0 Hz, 1H), 8.92 (d, J = 1.0 Hz, 1H), 7.82-7.91 (m, 2H),7.78 (t, J = 7.8 Hz, 1H), 4.44 (s, 2H), 3.40-3.52 (m, 2H), 2.96-3.09 (m,2H), 1.81-1.94 (m, 2H), 1.62-1.78 (m, 2H), 1.36-1.50 (m, 1H), 1.20-1.34(m, 1H). 62

  3-(4-Piperidin-1-ylmethyl-3- trifluoromethoxy-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile G D B⁴ 6.91, 452, A(DMSO-D₆, 400 MHz): 12.96 (br s, 1H), 9.14 (d, J = 2.3 Hz, 1H), 9.06-9.04 (m, 2H), 8.95 (d, J = 1.1 Hz, 1H), 7.86 (dd, J = 8.0, 1.8 Hz, 1H),7.76-7.74 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 3.55 (s, 2H), 2.43-2.35 (m,4H), 1.57-1.48 (m, 4H), 1.46- 1.36 (m, 2H). 63

  3-(3-Methoxy-5-piperidin-1- ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B⁴ 6.37, 398, A (CDCl₃ plusDMSO-D₆, 400 MHz): 9.02 (s, 1H), 8.91-8.87 (m, 1H), 8.70-8.66 (m, 1H),8.48 (s, 1H), 7.24 (s, 1H), 7.09 (s, 1H), 6.99 (s, 1H), 3.92 (s, 3H),3.57 (s, 2H), 2.53-2.39 (s, 4H), 1.69-1.58 (m, 4H), 1.54- 1.42 (m, 2H).64

  3-[4-(3-Hydroxy-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B⁴ 5.39, 384, A (DMSO-D₆, 400 MHz):12.91 (s, 1H), 9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H), 9.02(d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H),7.46 (d, J = 8.0 Hz, 2H), 4.58 (d, J = 4.8 Hz, 1H), 3.58 (d, J = 13.3Hz, 1H), 3.53-3.43 (m, 2H), 2.83 (dd, J = 10.4, 3.9 Hz, 1H), 2.72-2.65(m, 1H), 1.94-1.86 (m, 1H), 1.85-1.78 (m, 1H), 1.77- 1.70 (m, 1H),1.67-1.59 (m, 1H), 1.51-1.38 (m, 1H), 1.13-1.02 (m, 1H). 65

  3-[4-(4-Fluoro-piperidin-1-ylmethyl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B⁴ 5.95, 386, A (DMSO-D₆, 400 MHz):12.91 (s, 1H), 9.08 (d, J = 2.3 Hz, 1H), 9.05 (d, J = 1.1 Hz, 1H), 9.02(d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 7.8 Hz, 2H),7.47 (d, J = 7.8 Hz, 2H), 4.81-4.60 (m, 1H), 3.55 (s, 2H), 2.62-2.49 (m,2H), 2.39- 2.28 (m, 2H), 1.96-1.80 (m, 2H), 1.80-1.67 (s, 2H). 66

  3-(2-Ethyl-1,2,3,4-tetrahydro- isoquinolin-7-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B⁴ 5.53, 354, A (DMSO-D₆, 400 MHz):12.86 (s, 1H), 9.05 (d, J = 2.3 Hz, 1H), 9.03 (d, J = 1.1 Hz, 1H), 8.98(d, J = 2.3 Hz, 1H), 8.93 (d, J = 1.1 Hz, 1H), 7.56 (dd, J = 7.9, 1.9Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 3.65 (s,2H), 2.90-2.83 (m, 2H), 2.73-2.66 (m, 2H), 2.57- 2.51 (m, 2H), 1.13 (t,J = 7.2 Hz, 3H). 67

  3-(2-Ethyl-1,2,3,4-tetrahydro- isoquinolin-6-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 5.68, 354, A (CDCl₃ plus CD₃OD,400 MHz): 9.01 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.66 (d, J= 2.2 Hz, 1H), 8.48 (d, J = 1.0 Hz, 1H), 7.47-7.42 (m, 2H), 7.22 (d, J =7.8 Hz, 1H), 3.78 (s, 2H), 3.13-3.02 (m, 2H), 2.94-2.83 (m, 2H),2.76-2.65 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H) 68

  3-[4-(4-Trifluoromethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile GD B 6.58, 436, A (CDCl₃ plus CD₃OD, 400 MHz): 9.02 (d, J = 1.0 Hz, 1H),8.89 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 1.0 Hz,1H), 7.64 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 3.61 (s, 2H),3.08-3.01 (m, 2H), 2.11-1.99 (m, 3H), 1.91-1.83 (m, 2H), 1.75-1.61 (m,2H). 69

  3-(4-[1,4]Oxazepan-4-ylmethyl- phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 5.68, 384, A (CDCl₃ plus CD₃OD,400 MHz): 9.02 (s, 1 H), 8.90 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz,1H), 8.48 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 7.7 Hz, 2H),3.87 (t, J = 6.1 Hz, 2H), 3.81-3.74 (m, 4H), 2.84- 2.69 (m, 4H),2.02-1.90 (s, 2H). 70

  3-[4-(2-Aza-bicyclo[2.2.1]hept-2- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 6.11, 380, A (CDCl₃ plus CD₃OD,400 MHz): 9.03-9.00 (m, 1H), 8.91-8.88 (m, 1H), 8.70-8.67 (m, 1H),8.50-8.48 (m, 1H), 7.64 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H),3.80-3.68 (m, 2H), 3.18 (s, 1H), 2.86-2.80 (m, 1H), 2.41 (s, 1H), 2.34(d, J = 9.3 Hz, 1H), 1.93-1.83 (m, 1H), 1.79-1.72 (m, 1H), 1.68-1.56 (m,1H), 1.53- 1.43 (m, 1H), 1.42-1.39 (m, 2H). 71

  3-(4-Azepan-1-ylmethyl-phenyl)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 6.36, 382, A (CDCl₃ plus CD₃OD, 400 MHz):9.02-9.00 (m, 1H), 8.91-8.89 (m, 1H), 8.71-8.68 m, 1H), 8.50-8.48 (m,1H), 7.66-7.62 (m, 2H), 7.53- 7.49 (m, 2H), 3.74 (s, 2H), 3.42-3.35 (m,4H), 2.74-2.67 (m, 5H), 1.74- 1.62 (m, 3H). 72

  3-[4-(8-Aza-bicyclo[3.2.1]oct-8- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 6.31, 394, A (CDCl₃ plus CD₃OD,400 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.69 (d, J= 2.2 Hz, 1H), 8.49 (d, J = 1.0 Hz, 1H), 7.66-7.62 (m, 2H), 7.58-7.53(m, 2H), 3.64- 3.59 (m, 2H), 3.26-3.21 (m, 2H), 2.14-1.99 (m, 2H),1.86-1.75 (m, 2H), 1.71-1.64 (m, 2H), 1.63-1.46 (m, 2H), 1.44-1.36 (m,2H). 73

  3-[4-(4-Methoxy-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 5.89, 398, A (CDCl₃ plus CD₃OD,400 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.69 (d, J= 2.2 Hz, 1H), 8.50 (d, J = 1.0 Hz, 1H), 7.67-7.60 (m, 2H), 7.49 (d, J =8.0 Hz, 2H), 3.60 (s, 2H), 3.36 (s, 3H), 3.33-3.24 (m, 2H), 2.30-2.21(m, 2H), 1.99- 1.89 (m, 2H), 1.71-1.60 (m, 2H). 74

  3-[4-(4-Hydroxy-4-methyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile GD B 5.69, 398, A (CDCl₃ plus CD₃OD, 400 MHz): 9.02-9.01 (m, 1H), 8.90(d, J = 2.2 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 1.0 Hz, 1H),7.66-7.62 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 3.16 (s, 1H),2.64-2.56 (m, 2H), 2.55-2.46 (m, 2H), 1.75- 1.60 (m, 4H), 1.26 (s, 3H).75

  1-[4-(6-Cyano-9H-dipyrido[2,3- b;4′,3′-d]pyrrol-3-yl)-benzyl]-piperidine-4-carboxylic acid amide G D B 5.58, 411, A (DMSO-D₆, 400MHz): 12.89 (s, 1H), 9.08 (d, J = 2.2 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H),9.02 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.77 (d, J = 7.8 Hz,2H), 7.46 (d, J = 7.9 Hz, 2H), 7.20 (s, 1H), 6.70 (s, 1H), 3.52 (s, 2H),2.89-2.82 (m, 2H), 2.11-2.01 (m, 1H), 2.00-1.89 (m, 2H), 1.72-1.64 (m,2H), 1.63-1.50 (m, 2H). 76

  3-[4-(2-Oxa-7-aza-spiro[3.5]non-7- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 5.77, 410, A (CDCl₃ plusCD₃OD, 400 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.90 (d, J = 2.2 Hz, 1H),8.69 (d, J = 2.2 Hz, 1H), 8.49 (d, J = 1.0 Hz, 1H), 7.67-7.62 (m, 2H),7.48 (d, J = 8.0 Hz, 2H), 4.45 (s, 4H), 3.56 (s, 2H), 2.48-2.31 (m, 4H),1.97-1.87 (m, 4H). 77

  3-[4-(4-Cyano-piperidin-1-ylmethyl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 5.86, 393, A (CDCl₃ plus CD₃OD,400 MHz): 9.02 (d, J = 1.1 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.68 (d, J= 2.2 Hz, 1H), 8.48 (d, J = 1.1 Hz, 1H), 7.67-7.61 (m, 2H), 7.48 (d, J =8.0 Hz, 2H), 3.61 (s, 2H), 2.77-2.66 (m, 3H), 2.49-2.36 (s, 2H),2.03-1.86 (m, 4H). 78

  3-(3-Methyl-3H-imidazol-4-yl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D L, G 4.33, 275, A (DMSO-D₆, 300 MHz): 12.98 (br s,1H), 9.06 (s, 1H), 8.96 (s, 1H), 8.92 (s, 1H), 8.83 (s, 1H), 7.81 (s,1H), 7.20 (s, 1H), 3.76 (s, 3H). 79

  3-Imidazol-1-yl-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrileBuchwald A D L⁴ 4.16, 261, A (DMSO-D₆, 300 MHz): 13.35 (s, 1H), 9.70 (s,1H), 9.21 (d, J = 2.6 Hz, 1H), 9.15 (s, 1H), 9.12 (d, J = 2.6 Hz, 1H),8.92 (s, 1H), 8.32 (s, 1H), 7.99 (s, 1H). 80

  3-(1-Methyl-1H-pyrazol-3-yl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D L⁴ 7.44, 275, A (DMSO-D₆, 300 MHz): 12.88(br s, 1H), 9.14 (s, 2H), 9.02 (s, 1H), 8.98 (s, 1H), 7.82 (s, 1H), 6.84(s, 1H), 3.94 (s, 3H). 81

  3-(2-Methyl-2H-[1,2,4]triazol-3-yl)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D L⁴ 6.05, 276, A (DMSO-D₆, 300 MHz): 13.16(br s, 1H), 9.24-9.19 (m, 1H), 9.13-9.06 (m, 2H), 9.03 (s, 1H), 8.10 (s,1H), 4.09 (s, 3H). 82

  3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)- 9H-dip

do[2,3-b;4′,3′-d]pyrrole-6- carbonitrile F D A⁴ 9.72, 329, A (DMSO-D₆,300 MHz): 12.86 (br s, 1H), 8.87-9.07 (m, 4H), 7.28 (d, J = 2.2 Hz, 1H),7.23 (dd, J = 8.4, 2.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.27 (s, 4H).83

  3-(1H-Imidazol-2-yl)-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrileA D L, B 4.32, 261, A (DMSO-D₆, 400 MHz): 12.93 (s, 1H), 12.74 (s, 1H),9.26 (m, 2H), 9.05 (d, J = 1.1 Hz, 1H), 8.96 (d, J = 1.1 Hz, 1H), 7.34(s, 1H), 7.12 (s, 1H). 84

  3-(2-Ethyl-8-methoxy-1,2,3,4- tetrahydro-isoquinolin-6-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile A D L, B 6.04, 384, A(CDCl₃ plus CD₃OD, 400 MHz): 9.01 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 2.2Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.50 (d, J = 1.0 Hz, 1H), 7.03 (d, J= 1.3 Hz, 1H), 6.92 (d, J = 1.6 Hz, 1H), 3.94 (s, 3H), 3.67 (s, 2H),3.03 (t, J = 5.9 Hz, 2H), 2.81 (t, J = 5.9 Hz, 2H), 2.70 (q, J = 7.2 Hz,2H), 1.26 (t, J = 7.2 Hz, 3H). 85

  3-[4-((3S,5R)-3,5-Dimethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile AD L, B 6.68, 396, A (DMSO-D₆ plus TFA-D, 400 MHz): 13.00 (s, 1H), 9.15(d, J = 2.3 Hz, 1H), 9.09 (d, J = 2.3 Hz, 1H), 9.07 (d, J = 1.1 Hz, 1H),8.94 (d, J = 1.1 Hz, 1H), 7.94 (d, J = 7. 9 Hz, 2H), 7.75 (d, J = 8.0Hz, 2H), 4.39-4.32 (m, 2H), 3.34-3.26 (m, 2H), 2.05- 1.91 (m, 2H),1.80-1.72 (m, 1H), 0.90 (s, 3H), 0.89 (s, 3H). 86

  3-[4-(4-Morpholin-4-yl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D E⁵ 4.7, 453, A (CDCl₃, 400 MHz):10.17 (s, 1H), 9.09 (s, 1H), 8.97-8.96 (m, 1H), 8.65 (dd, J = 2.2, 0.9Hz, 1H), 8.45 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 3.73 (t, J = 4.4 Hz, 4H), 3.59 (s, 2H), 3.04-2.97 (m, 2H), 2.57 (t,J = 4.4 Hz, 4H), 2.28-2.18 (m, 1H), 2.09-1.99 (m, 2H), 1.88-1.80 (m,2H), 1.67-1.53 (m, 2H). 87

  3-[4-(4-Dimethylamino-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D E³ 4.6, 411, A (DMSO-D₆, 400 MHz):12.84 (br s, 1H), 9.08 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H),9.02 (d, J = 2.3 Hz, 1H), 8.95 (d, J = 1.0 Hz, 1H), 7.76 (d, J = 8.0 Hz,2H), 7.46 (d, J = 8.0 Hz, 2H), 3.51 (s, 2H), 2.90-2.83 (m, 2H), 2.17 (s,6H), 2.10-2.01 (m, 1H), 2.00-1.90 (m, 2H), 1.76-1.67 (m, 2H), 1.45-1.31(m, 2H). 88

  3-[4-(2,2-Dimethyl-morpholin-4- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G^(a) D R, B³ 5.95, 398, A (CDCl₃ plusCD₃OD, 300 MHz): 9.02 (d, J = 1.0 Hz, 1H), 8.93 (d, J = 2.2 Hz, 1H),8.83 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 1.1 Hz, 1H), 7.69 (d, J = 8.0 Hz,2H), 7.52 (d, J = 8.0 Hz, 2H), 3.83-3.78 (m, 2H), 3.57 (s, 2H),2.53-2.45 (m, 2H), 2.28 (s, 2H), 1.29 (s, 6H). 89

  3-[4-((2R,6S)-2,6-Dimethyl-morpholin-4-ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrileG^(a) D B³ 5.98, 398, A (CDCl₃ plus CD₃OD, 300 MHz): 9.02 (d, J = 1.0Hz, 1H), 8.93 (d, J = 2.2 Hz, 1H), 8.80 (d, J = 2.2 Hz, 1H), 8.61 (d, J= 1.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H),3.83-3.69 (m, 2H), 3.61 (s, 2H), 2.85-2.76 (m, 2H), 1.92-1.80 (m, 2H),1.18 (d, J = 6.3 Hz, 6H). 90

  3-(4-((2R,6S)-2,6-Dimethyl-morpholin- 4-ylmethyl)-3-ethoxy-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile G^(a) D R, B 7.51, 442, F(CDCl₃ plus CD₃OD, 300 MHz): 9.02 (d, J = 1. Hz, 1H), 8.92 (d, J = 2.2Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.64 (d, J = 1.1 Hz, 1H), 7.47 (d, J= 7.8 Hz, 1H), 7.28 (dd, J = 7.7, 1.7 Hz, 1H), 7.21 (d, J = 1.7 Hz, 1H),4.22 (q, J = 7.0 Hz, 2H), 3.82-3.69 (m, 2H), 3.68 (s, 2H), 2.89-2.80 (m,2H), 1.99-1.88 (m, 2H), 1.51 (t, J = 7.0 Hz, 3H), 1.18 (d, J = 6.3 Hz,6H). 91

  3-(4,5,6,7-Tetrahydrobenzo[b] thiophen-2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F D A, H⁷ 12.5, 331, A; (DMSO-D₆, 300MHz): 12.90 (s, 1H), 9.02 (d, J = 1.1 Hz, 1H), 8.95 (d, J = 2.3 Hz, 2H),8.93 (d, 2.3 Hz, 1H), 7.29 (s, 1H), 2.81-2.74 (m, 2H), 2.66-2.60 (m,2H), 1.88-1.73 (m, 4H). 92

  4-(6-Cyano-9H-dipyrido[2,3-b;4′,3′- d]pyrrol-3-yl)-benzoic acid F^(b)D B⁹, H⁹ 7.93, 315, A (DMSO-D₆, 300 MHz): 13.00 (s, 1H), 9.20 (d, J =2.2 Hz, 1H), 9.10 (d, J = 2.2 Hz, 1H), 9.06 (s, 1H), 8.96 (s, 1H), 8.11(d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H). 93

  3-[4-(2-Oxa-6-aza-spiro[3.3]hept-6- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F^(c) D H³ 5.57, 382, A (DMSO-D₆, 400MHz): 12.90 (s, 1H), 9.07 (d, J = 2.3 Hz, 1H), 9.04 (d, J = 1.1 Hz, 1H),9.01 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.75 (d, J = 8.0 Hz,2H), 7.41 (d, J = 8.0 Hz, 2H), 4.63 (s, 4H), 3.56 (s, 2H). 94

  3-[4-(2-Piperidin-1-yl-ethyl)-phenyl]- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B,³ 6.23, 382, A (CDCl₃ plus CD₃OD, 400MHz): 9.01 (d, J = 1.0 Hz, 1 H), 8.88 (d, J = 2.2 Hz, 1H), 8.67 (d, J =2.2 Hz, 1 H), 8.49 (d, J = 1.0 Hz, 1H), 7.62-7.57 (m, 2H), 7.41-7.36 (m,2H), 2.95- 2.87 (m, 2H), 2.68-2.61 (m, 2H), 2.54 (s, 4H), 1.71-1.62 (m,4H), 1.56-1.46 (m, 2H). 95

  (Z)-3-{5-[4-(3-Hydroxy-3-methyl- piperidin-1-ylmethyl)-phenyl]-2-methyl-1H-pyrrolo[2,3-b]pyridin- 3-yl}-2-methyleneamino-acrylonitrile GD E 5.48, 416 (M + 18), A (DMSO-D₆, 400 MHz): 9.08 (d, J = 2.3 Hz, 1H),9.04 (d, J = 1.1 Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz,1 H), 7.76 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 4.36 (s, 1H),3.81 (s, 2H), 3.40-3.34 (m, 2H), 2.42 (s, 2H), 1.46-1.38 (m, 4H), 1.08(s, 3H). 96

  3-[4-(4-Methoxy-4-methyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile GD B 6.27, 412 (M + 18), A (CDCl₃ plus CD₃OD, 400 MHz): 9.01 (d, J = 1.0Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.48 (d, J= 1.1 Hz, 1H), 7.66-7.62 (m, 2H), 7.52-7.48 (m, 2H), 3.60 (s, 2H), 3.20(s, 3H), 2.63-2.55 (m, 2H), 2.46-2.36 (m, 2H), 1.85-1.76 (m, 2H),1.65-1.55 (m, 2H), 1.18 (s, 3H). 97

  3-(4-Thiomorpholin-4-ylmethyl- phenyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 5.98, 386, A (CDCl₃ plus CD₃OD, 400 MHz):9.02 (d, J = 1.0 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.67 (d, J = 2.2 Hz,1H), 8.47 (d, J = 1.1 Hz, 1H), 7.66-7.61 (m, 2H), 7.51-7.46 (m, 2 H),3.62 (s, 2H), 2.81-2.76 (m, 4H), 2.75-2.69 (m, 4H). 98

  3-[4-(1,1-Dioxo-1lambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′- d]pyrrole-6-carbonitrile G D L, B^(3,1)7.43, 418, A (DMSO-D₆, 400 MHz): 12.91 (s, 1H), 9.09 (d, J = 2.3 Hz,1H), 9.05 (d, J = 1.1 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H), 8.94 (d, J =1.1 Hz, 1H), 7.82-7.77 (m, 2H), 7.54-7.49 (m, 2H), 3.76 (s, 2H),3.18-3.10 (m, 4H), 2.97-2.89 (m, 4H). 99

  3-[4-(1-Oxo-thiomorpholin-4- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile G D B 5.34, 402, A(DMSO-D₆, 400 MHz): 12.91 (s, 1H), 9.09 (d, J = 2.3 Hz, 1H), 9.05 (d, J= 1.1 Hz, 1H), 9.03 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H),7.81-7.76 (m, 2H), 7.53-7.48 (m, 2H), 3.66 (s, 2H), 2.97-2.84 (m, 4H),2.82-2.62 (m, 4H). 100

  3-[4-(3-Oxo-piperazin-1-ylmethyl)- phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B 5.50, 383, A (CDCl₃ plus CD₃OD, 400 MHz):9.02 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H), 8.53(s, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 3.70 (s,2H), 3.42-3.36 (m, 2H), 3.20 (s, 2H), 2.76-2.71 (m, 2H). 101

  3-(4-Diethylaminomethyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B, B³ 5.90, 356, A (CDCl₃, 400 MHz): 10.27 (s, 1H),9.09 (s, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H), 8.45(s, 1H), 7.63 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 3.68 (s,2H), 2.66-2.54 (m, 4H), 1.11 (t, J = 7.1 Hz, 6H). 102

  3-[4-((S)-3-Hydroxy-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B, B³ 5.45, 384, A (CDCl₃ plusCD₃OD, 400 MHz): 9.02-9.00 (m, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.70 (d, J= 2.2 Hz, 1H), 8.51 (d, J = 1.0 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.48(d, J = 7.9 Hz, 2H), 3.85-3.73 (m, 1H), 3.62 (s, 2H), 2.84-2.72 (m, 1H),2.64-2.52 (m, 1H), 2.37-2.18 (m, 2H), 1.89-1.74 (m, 2H), 1.67-1.52 (m,1H), 1.48- 1.34 (m, 1H). 103

  3-[4-((R)-3-Hydroxy-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D B, B³ 5.54, 384, A (CDCl₃ plusCD₃OD, 400 MHz): 9.02-9.00 (m, 1H), 8.90-8.87 (m, 1H), 8.70-8.66 (m,1H), 8.50-8.48 (m, 1H), 7.66-7.61 (m, 2H), 7.50- 7.45 (m, 2H), 3.84-3.75(m, 1H), 3.61 (s, 2H), 2.79-2.70 (m, 1H), 2.59-2.50 (m, 1H), 2.37-2.22(s, 2H), 1.85-1.75 (m, 2H), 1.64-1.52 (m, 1H), 1.48-1.37 (m, 1H). 104

  3-[4-((3S,5S)-3,5-Dimethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile GD B 7.17, 396, F (DMSO-D₆, 400 MHz): 12.89 (s, 1H), 9.08 (d, J = 2.3 Hz,1H), 9.04 (d, J = 1.1 Hz, 1H), 9.02 (d, J = 2.3 Hz, 1H), 8.93 (d, J =1.1 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H),3.54-3.40 (m, 2H), 2.44- 2.35 (m, 2H), 2.12-1.98 (m, 2H), 1.94-1.82 (m,2H), 1.31-1.24 (m, 2H), 0.94 (d, J = 6.8 Hz, 6H). 105

  3-(6-Piperidin-1-ylmethyl-pyridin-3- yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile F B R³ 5.51, 369, A (DMSO-D₆, 400 MHz): 12.99 (s,1H), 9.16 (dd, J = 5.4, 2.3 Hz, 1H), 9.09-9.07 (m, 2H), 8.95-8.93 (m,2H), 8.21 (dd, J = 8.1, 2.5 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 3.64 (s,2H), 2.44 (s, 4H), 1.56 (p, J = 5.5 Hz, 4H), 1.47-1.41 (m, 2H). 106

  3-(5-Piperidin-1-ylmethyl-pyridin-2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile F B R⁶ 5.46, 369, A(DMSO-D₆, 400 MHz): 12.99 (s, 1H), 9.48 (d, J = 2.2 Hz, 1H), 9.43 (d, J= 2.2 Hz, 1H), 9.07 (d, J = 1.1 Hz, 1H), 9.04 (s, 1H), 8.65 (d, J = 2.1Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.89 (dd, J = 8.2, 2.2 Hz, 1H), 3.55(s, 2H), 2.36 (s, 4H), 1.58-1.50 (m, 4H), 1.43 (d, J = 7.0 Hz, 2H). 107

  3-(3-Chloro-4-piperidin-1-ylmethyl- phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile G D R^(3/7) 6.38, 402, A (CD₃OD, 400 MHz): 8.83(d, J = 2.1 Hz, 1H), 8.70 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.08 (s,1H), 7.92 (s, 1H), 4.71 (t, J = 6.1 Hz, 2H), 4.02 (s, 3H), 2.89 (t, J =7.8 Hz, 2H), 2.66 (s, 4H), 2.33-2.23 (m, 2H), 1.88-1.83 (m, 4H). 108

  3-(6-Ethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile HD B 5.62, 360, A (DMSO-D₆, 400 MHz): 12.90 (br s, 1H); 9.02 (d, J = 1.1Hz, 1H); 8.96 (d, J = 2.3 Hz, 1H); 8.95 (d, J = 1.1 Hz, 1H); 8.93 (d, J= 2.3 Hz, 1H); 7.33 (s, 1H); 3.64 (s, 2H); 2.76-2.66 (m, 4H); 2.57 (q, J= 7.2 Hz, 2H); 1.11 (t, J = 7.15 Hz, 3H).^(a)1-1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) used ascatalyst ^(b)Aryl iodide used in coupling ^(c)THF used as solvent

indicates data missing or illegible when filed

The compounds of the Examples in Table 5 were prepared from commerciallyavailable amines using the general Mesylate Displacement Methodsdescribed above.

TABLE 5 LCMS Depro- Puri- R_(T), Mesylate tec- fica- M + Ex- displace-tion tion H⁺, am- ment Meth- Meth- Meth- ple Structure/Name Method odod(s) od ¹H NMR (ppm) 109

  3-[4-((3S,5R)-3,5-Dimethyl-piperidin- 1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA B 6.10, 396, A (CDCl₃, 400MHz): 9.00 (dd, J = 1.1, 0.5 Hz, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.71 (d,J = 2.2 Hz, 1H), 8.51 (dd, J = 1.1, 0.5 Hz, 1H), 7.65 (d, J = 8.0 Hz,2H), 7.49 (d, J = 8.0 Hz, 2H), 3.60 (s, 2H), 2.91-2.88 (m, 1H),2.90-2.84 (m, 1H), 1.79-1.68 (m, 4H), 1.55 (t, J = 11 Hz, 2H), 0.86 (d,J = 6.4 Hz, 6H). 110

  3-[4-(4,4-Dimethyl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA B 6.60, 396, A (CDCl₃, 400MHz): 9.01 (s, 1H), 8.91 (d, J = 2.2 Hz, 1H), 8.72 (d, J = 2.2 Hz, 1H),8.52 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 3.65(s, 2H), 2.56-2.48 (m, 4H), 1.47 (t, J = 5.6 Hz, 4H), 0.96 (s, 6H). 111

  3-[4-(3,3-Dimethyl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA L 6.34, 396, A (CDCl₃, 300MHz): 10.69 (s, 1H), 9.12 (d, J = 1.1 Hz, 1H), 9.00 (d, J = 2.1 Hz, 1H),8.68 (d, J = 2.1 Hz, 1H), 8.46 (d, J = 1.0 Hz, 1H), 7.63 (d, J = 8.1 Hz,2H), 7.52 (d, J = 8.0 Hz, 2H), 3.53 (s, 2H), 2.43-2.35 (m, 2H),2.09-2.05 (m, 2H), 1.68-1.57 (m, 2H), 1.26 (t, J = 6.8 Hz, 2H), 0.97 (s,6H). 112

  3-[4-(2,2-Dimethyl-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B D B 2.31, 396, A (CDCl₃, 400MHz): 10.07 (br. s, 1H), 9.09 (d, J = 1.0 Hz, 1H), 8.96 (d, J = 2.1 Hz,1H), 8.64 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 1.0 Hz, 1H), 7.61 (d, J =7.7 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 3.59 (s, 2H), 2.44-2.39 (m, 2H),1.52 (m, 2H), 1.38-1.30 (m, 2H), 1.16 (s, 6H), 0.94 (t, J = 7.3 Hz, 2H).113

  3-[4-(4-Hydroxy-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA B 5.41, 384, A (CDCl₃, 400MHz): 9.02 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H),8.52 (m, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H),3.72-3.63 (m, 1H), 3.63 (s, 2H), 2.90-2.83 (m, 2H), 2.30- 2.20 (m, 2H),1.95-1.86 (m, 2H), 1.68-1.57 (m, 2H). 114

  3-[4-(3-Hydroxy-pyrrolidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA B 5.41, 370, A (CDCl₃, 400MHz): 9.02 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.71 (d, J = 2.2 Hz, 1H),8.52 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 7.9 Hz, 2H),4.44-4.38 (m, 1H), 3.81 (s, 2H), 3.74-3.54 (br. m, 1H), 2.94 (q, J = 8.0Hz, 1H), 2.89- 2.81 (m, 1H), 2.77-2.69 (m, 1H), 2.66-2.55 (m, 1H), 2.25(dt, J = 14.1, 7.0 Hz, 1H), 1.85-1.76 (m, 1H). 115

  3-{4-[4-(2-Hydroxy-ethyl)-piperidin-1-ylmethyl]-phenyl)-9H-dipyrido[2, 3-b;4′,3′-d]pyrrole-6-carbonitrile ANA B⁶ 5.62, 412, A (CD₃OD, 400 MHz): 9.01 (d, J = 1.0 Hz, 1H), 8.97 (d,J = 2.2 Hz, 1H), 8.95 (d, J = 2.2 Hz, 1H), 8.75 (d, J = 1.0 Hz, 1H),7.82 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H), 4.53 (s, 1H), 3.99(s, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.28-3.19 (m, 2H), 2.72 (s, 1H),2.68-2.49 (m, 2H), 1.94-1.82 (m, 2H), 1.70-1.60 (m, 2H), 1.52 (q, J =6.5 Hz, 2H), 1.47-1.34 (m, 2H). 116

  3-[4-(4,4-Difluoro-piperidin-1- ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C D L 5.93, 404, A (DMSO-D₆, 400 MHz):12.91 (s, 1H), 9.08 (d, J = 2.3 Hz, 1H), 9.05 (d, J = 1.1 Hz, 1H), 9.02(d, J = 2.3 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H),7.49 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 2.58- 2.51 (m, 4H), 2.05-1.92(m, 4H).

The compounds of the Examples in Table 6 were prepared from alkynesusing the general Sonagashira Method described above.

TABLE 6 Depro- Puri- LCMS Ex- Sonagashira tec- fica- R_(T), am- couplingtion tion M + H⁺, ple Structure/Name Method Method Method(s) Method ¹HNMR (ppm) 117

  3-(3-Dimethylamino-prop-1-ynyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA M 4.60, 276, A (CDCl₃, 400 MHz): 9.18 (d, J = 1.2 Hz,1H), 8.74 (d, J = 2.3 Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 1Hz, 1H), 5.98 (s, 1H), 3.56-3.60 (m, 2H), 0.94- 0.98 (m, 2H), 0.08 (s,9H). 118

  3-Piperidin-4-ylethynyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A A I 5.22, 302, A (DMSO-D₆, 400MHz): 9.02 (d, J = 1.1 Hz, 1H), 8.87 (d, J = 1.0 Hz, 1H), 8.82 (d, J =2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 3.00-2.93 (m, 2H), 2.83-2.74 (m,1H), 2.65-2.57 (m, 2H), 1.88- 1.82 (m, 2H), 1.61-1.50 (m, 2H). 119

  3-Piperidin-3-ylethynyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A A I 5.25, 302, A (DMSO-D₆, 400MHz): 9.02 (d, J = 1.1 Hz, 1H), 8.88 (d, J = 1.1 Hz, 1H), 8.82 (d, J =2.1 Hz, 1H), 8.68 (d, J = 2.1 Hz, 1H), 3.10 (d, J = 10.6 Hz, 1H), 2.84-2.77 (m, 1H), 2.71-2.52 (m, 3H), 2.09-1.99 (m, 1H), 1.69-1.55 (m, 2H),1.46-1.36 (m, 1H).

The compounds of the Examples in Table 7 were prepared from commerciallyavailable phenols or aryl bromides using the general Ullmann Methodsdescribed above.

TABLE 7 Puri- LCMS fica- R_(T), Ex- Ullmann Depro- tion M + am- Couplingtection Meth- H⁺, ple Structure/Name Method Method od(s) Method ¹H NMR(ppm) 120

  3-(3,5-Dimethoxy-phenoxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A D I 10.1, 347, A (DMSO-D₆, 400 MHz): 13.09 (s, 1H), 9.03(d, J = 1.1 Hz, 1H), 8.91 (d, J = 1.1 Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H),8.55 (d, J = 2.7 Hz, 1H), 6.31 (t, J = 2.2 Hz, 1H), 6.20 (d, J = 2.2 Hz,2H), 3.71 (s, 6H). 121

  3-(3-Piperazin-1-yl-phenoxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A A B 6.1, 371, A (DMSO-D₆, 400 MHz): 8.98 (d, J = 1.1 Hz,1H), 8.88 (s, 1H), 8.84 (d, J = 1.1 Hz, 1H), 8.52 (d, J = 2.7 Hz, 1H),8.46 (d, J = 2.7 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 6.73 (dd, J = 8.3,2.3 Hz, 1H), 6.69 (t, J = 2.3 Hz, 1H), 6.43 (dd, J = 8.1, 2.2 Hz, 1H),3.33-3.28 (m, 4H), 3.18-3.12 (m, 4H). 122

  3-(4-Morpholin-4-ylmethyl-phenoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile B A B 5.7, 386, A(DMSO-D₆, 300 MHz): 9.03 (d, J = 1.0 Hz, 1H), 8.90 (d, J = 1.0 Hz, 1H),8.59 (d, J = 2.7 Hz, 1H), 8.54 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 8.3 Hz,2H), 7.02 (d, J = 8.3 Hz, 2H), 3.57 (t, J = 4.5 Hz, 4H), 3.44 (s, 2H),2.35 (t, J = 4.2 Hz, 4H). 123

  3-(4-Piperidin-1-ylmethyl-phenoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile B D B 6.0, 384, A(DMSO-D₆, 300 MHz): 9.03 (d, J = 1.0 Hz, 1H), 8.90 (d, J = 1.0 Hz, 1H),8.59 (d, J = 2.7 Hz, 1H), 8.54 (d, J = 2.7 Hz, 1H), 7.30 (d, J = 8.4 Hz,2H), 7.02 (t, J = 8.4 Hz, 2H), 3.40 (s, 2H), 2.35-2.27 (m, 4H),1.54-1.43 (m, 4H), 1.43-1.33 (d, J = 7.2 Hz, 2H).

The compounds of the Examples in Table 8 were prepared from commerciallyavailable boronic acids.

TABLE 8 LCMS Ex- R_(T)/ am- Coupling Purification M + H⁺/ pleStructure/Name Method Method(s) Method ¹H NMR (ppm) 124

  3-(4-Fluoro-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileA B, H 9.94, 289, A (DMSO-D₆, 300 MHz): 12.96 (s, 1H), 9.09-9.00 (m,3H), 8.95-8.90 (m, 1H), 7.86 (dd, J = 8.7, 5.5 Hz, 2H), 7.46-7.33 (m,2H). 125

  3-[4-(4-Methyl-piperazin-1-yl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A B 5.66, 369, A (DMSO-D₆, 300 MHz):12.84 (s, 1H), 9.03-8.93 (m, 4H), 7.67 (d, J = 8.7 Hz, 2H), 7.10 (d, J =8.7 Hz, 2H), 3.22 (m, 4H), 2.54- 2.46 (m, 4H), 2.24 (s, 3H). 126

  3-(1-Methyl-1H-pyrazol-4-yl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A G⁴ 6.90, 275, A (DMSO-D₆, 300 MHz): 12.79 (s, 1H), 9.01(d, J = 1.1 Hz, 1H), 8.96 (d, J = 2.2 Hz, 1H), 8.92 (d, J = 2.2 Hz, 1H),8.84 (d, J = 1.1 Hz, 1H), 8.24 (s, 1H), 7.97 (s, 1H), 3.92 (s, 3H). 127

  3-[1-(2-Morpholin-4-yl-ethyl)-1H- pyrazo-4-yl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D D 5.0, 374, A (DMSO-D₆, 400 MHz):12.98 (s, 1H), 9.04-9.02 (m, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.96-8.94(m, 1H), 8.87 (d, J = 1.1 Hz, 1H), 8.32 (d, J = 0.8 Hz, 1H), 8.01 (d, J= 0.8 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.59 (t, J = 4.5 Hz, 4H), 2.79(t, J = 6.6 Hz, 2H), 2.46 (m, 4H). 128

  3-(1-Methyl-1H-imidazol-2-yl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile Stille A D 4.1, 275, A (DMSO-D₆, 400 MHz): 12.52 (br s,1H), 9.04 (d, J = 1.1 Hz, 1H), 8.94 (d, J = 1.1 Hz, 1H), 8.90 (d, J =2.2 Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H), 7.79-7.76 (m, 1H), 7.18 (d, J =1.1 Hz, 1H), 3.75 (s, 3H). 129

  3-(2-Methoxy-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Preparative HPLC 1.17, 301, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.01(s, 1H), 8.92 (s, 1H), 8.82 (s, 1H), 8.74 (s, 1H), 7.41-7.37 (m, 2H),7.16-7.14 (m, 1H), 7.09-7.07 (m, 1H), 3.77 (s, 3H) 130

  3-Phenyl-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile CPreparative HPLC 1.18, 271, C (DMSO-D₆, 400 MHz): 12.89 (s, 1H),9.06-9.01 (m, 3H), 8.99-8.91 (m, 1H), 7.79-7.77 (m, 2H), 7.54-7.50 (m,2H), 7.38-7.42 (m, 1H) 131

  3-(4-Methoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.42, 301, C (DMSO-D₆, 400MHz): 12.96 (s, 1H), 9.15-8.89 (m, 4H), 7.70 (br, 2H), 7.12 (br, 2H),3.75 (s, 3H) 132

  4-(6-Cyano-9H-dipyrido[2,3- b;4′,3′-d]pyrrol-3-yl)-N,N-diethyl-benzamide C Preparative HPLC 1.20, 370, C (DMSO-D₆, 400 MHz):12.96 (s, 1H), 9.11 (s, 1H), 9.10 (s, 2H), 8.91 (s, 1H), 7.85-7.83 (d, J= 8.0 Hz, 2H), 7.49-7.47 (d, J = 8.4 Hz, 2H), 3.30-3.10 (m, 4H),1.20-1.08 (m, 6H) 133

  3-m-Tolyl-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile CPreparative HPLC 1.25, 285, C (DMSO-D₆, 400 MHz): 12.90 (s, 1H),9.04-8.97 (m, 3H), 8.92 (s, 1H), 7.06-7.56 (m, 2H), 7.42-7.38 (m, 1H),7.23- 7.21 (m, 1H), 2.40 (s, 3H) 134

  3-(4-tert-Butyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.40, 327, C (DMSO-D₆, 400 MHz): 12.89(s, 1H), 9.03-9.02 (m, 2H), 8.98 (s, 1H), 8.93 (s, 1H), 7.73-7.71 (d, J= 8.4 Hz, 2H), 7.55-7.53 (d, J = 8.4 Hz, 2H), 1.32 (s, 9H) 135

  3-(4-Isopropoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.28, 329, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.01-8.91 (m, 4H), 7.70-7.68 (d, J = 8.4 Hz, 2H), 7.07-7.05 (d,J = 8.8 Hz, 2H), 4.71- 4.65 (m, 1H), 1.29-1.28 (d, J = 6.0 Hz, 6H) 136

  3-(3-Hydroxymethyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.26, 301, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.28 (m, 4H), 7.75 (s, 1H), 7.68-7.66 (m, 1H), 7.51- 7.48 (m,1H), 7.38-7.36 (m, 1H), 5.50 (br, 1H), 4.61 (s, 2H) 137

  3-p-Tolyl-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile CPreparative HPLC 1.24, 285, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H),9.04-8.93 (m, 4H), 7.70-7.68 (d, J = 8.0 Hz, 2H), 7.35-7.33 (d, J = 8.0Hz, 2H), 2.36 (s, 3H) 138

  N-[3-(6-Cyano-9H-dipyrido[2,3- b;4′,3′-d]pyrrol-3-yl)-phenyl]-acetamide C Preparative HPLC 1.27, 328, C (DMSO-D₆, 400 MHz): 12.96 (s,1H), 10.11 (s, 1H), 9.04-8.98 (m, 3H), 8.92 (s, 1H), 8.02 (s, 1H),7.59-7.56 (m, 1H), 7.48- 7.43 (m, 2H), 2.07 (s, 3H) 139

  3-(4-Methanesulfonyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.26, 349, C (DMSO-D₆, 400 MHz): 13.01(s, 1H), 9.21 (s, 1H), 9.11 (s, 1H), 9.06 (s, 1H), 8.95 (s, 1H),8.12-8.04 (m, 4H), 3.28 (s, 3H) 140

  3-(2-Hydroxy-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Preparative HPLC 1.05, 287, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.85(s, 1H), 9.09 (s, 1H), 9.02 (s, 1H), 8.96 (s, 1H), 8.91 (s, 1H),7.47-7.45 (m, 1H), 7.33-7.28 (m, 1H), 7.09-7.00 (m, 2H) 141

  3-(2-Hydroxymethyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.02, 301, C (DMSO-D₆, 400 MHz): 13.02(s, 1H), 9.13 (s, 1H), 9.00 (s, 1H), 8.87 (s, 1H), 8.79 (s, 1H), 7.66(m, 1H), 7.69-7.44 (m, 3H), 5.32-5.29 (m, 1H), 4.53- 4.52 (d, J = 5.2Hz, 2H) 142

  3-(2-Trifluoromethoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.25, 355, C (DMSO-D₆, 400 MHz): 13.05(s, 1H), 9.05 (s, 1H), 8.94 (s, 1H), 8.91 (s, 1H), 8.78 (s, 1H),7.70-7.67 (m, 1H), 7.63-7.53 (m, 3H) 143

  3-(3-Methylsulfanyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.24, 317, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.11 (s, 1H), 9.03 (s, 2H), 8.94 (s, 1H), 7.65 (s, 1H),7.58-7.56 (m, 1H), 7.45-7.49 (m, 1H), 7.32-7.30 (m, 1H), 2.57 (s, 3H)144

  3-Furan-2-yl-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile CPreparative HPLC 1.10, 261, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.06(s, 1H), 9.00-8.99 (m, 2H), 8.92 (s, 1H), 7.83 (s, 1H), 7.06-7.05 (d, J= 3.2 Hz, 1H), 6.65-6.55 (m, 1H) 144

  3-(4-Chloro-2-ethoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.30, 349, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.04 (s, 1H), 8.93-8.90 (m, 2H), 8.83 (s, 1H), 7.50 (s, 1H),7.42-7.39 (m, 1H), 7.18- 7.16 (d, J = 8.8 Hz, 1H), 4.10- 4.05 (m, 2H),1.28-1.24 (m, 3H) 145

  3-(4-Ethyl-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrile CPreparative HPLC 1.56, 299, C (DMSO-D₆, 400 MHz): 12.89 (s, 1H),9.04-9.02 (m, 2H), 8.98 (s, 1H), 8.92 (s, 1H), 7.72-7.70 (d, J = 8.0 Hz,2H), 7.38-7.36 (d, J = 8.4 Hz, 2H), 2.69-2.64 (m, 2H), 1.20-1.24 (m, 3H)146

  3-(3,4-Difluoro-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.48, 307, C(DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.11 (s, 1H), 9.04-9.03 (m, 2H), 8.89(s, 1H), 7.97-7.91 (m, 1H), 7.70-7.58 (m, 2H) 147

  3-(2-Ethyl-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrile CPreparative HPLC 1.27, 299, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.04(s, 1H), 8.93 (s, 1H), 8.74 (s, 1H), 8.83 (s, 1H), 7.40-7.36 (m, 2H),7.33-7.27 (m, 2H), 2.61-2.55 (m, 2H), 1.04-1.01 (m, 3H) 148

  3-(2-Fluoro-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Preparative HPLC 1.29, 289, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.02(s, 1H), 8.96-8.94 (m, 2H), 8.84 (s, 1H), 7.71-7.69 (m, 1H), 7.40-7.36(m, 1H), 7.37-7.35 (m, 2H) 149

  3-o-Tolyl-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile CPreparative HPLC 1.22, 285, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.04(s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.67 (s, 1H), 7.37-7.33 (m, 4H),2.29 (s, 3H) 150

  3-(4-Trifluoromethoxy-phenyl)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.56, 355, C (DMSO-D₆, 400MHz): 13.01 (s, 1H), 9.11 (s, 1H), 9.05-9.02 (m, 2H), 8.92 (s, 1H),7.94-7.92 (d, J = 8.4 Hz, 2H), 7.55-7.53 (d, J = 8.4 Hz, 2H) 151

  3-(4-Trifluoromethyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.54, 339, C (DMSO-D₆, 400 MHz): 9.25(s, 1H), 9.16-9.12 (m, 2H), 9.00 (s, 1H), 8.13-8.11 (d, J = 8.4 Hz, 1H),7.98-7.96 (d, J = 8.4 Hz, 1H) 152

  3-(4-Ethoxy-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Preparative HPLC 1.23, 315, C (DMSO-D₆, 400 MHz): 12.89 (s, 1H),9.02-9.00 (m, 2H), 8.96 (s, 1H), 8.92 (s, 1H), 7.73-7.71 (d, J = 8.8 Hz,2H), 7.08-7.07 (d, J = 8.8 Hz, 2H), 4.11-4.06 (m, 2H), 1.37-1.34 (m, 3H)153

  3-(4-Methylsulfanyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Washing with THF and methanol 1.24, 317, C (DMSO-D₆,400 MHz): 12.89 (s, 1H), 9.07 (s, 1H), 9.03 (s, 1H), 9.00 (s, 1H), 8.94(s, 1H), 7.77-7.75 (d, J = 8.4 Hz, 2H), 7.43-7.41 (d, J = 8.4 Hz, 2H),2.53 (s, 3H) 154

  3-(3-Chloro-4-ethoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.27, 323, C (DMSO-D₆, 400 MHz): 12.73(s, 1H), 8.89-8.82 (m, 3H), 8.72 (s, 1H), 7.71 (s, 1H), 7.58-7.55 (d, J= 8.4 Hz, 1H), 7.13-7.11 (d, J = 8.4 Hz, 1H), 4.04-3.99 (m, 2H),1.25-1.14 (m, 3H) 155

  3-(4-Fluoro-2-methoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.48, 319, C (DMSO-D₆, 400 MHz): 12.89(s, 1H), 9.03 (s, 1H), 8.94 (s, 1H), 8.83 (s, 1H), 8.74 (s, 1H),7.48-7.44 (m, 1H), 7.12-7.09 (m, 1H), 6.94-6.93 (m, 1H), 3.82 (s, 3H)156

  3-(3-Methoxy-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Preparative HPLC 1.44, 301, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.04(s, 1H), 8.99-8.96 (m, 2H), 8.88 (s, 1H), 7.42-7.39 (m, 1H), 7.32-7.28(m, 2H), 6.98-6.89 (m, 1H), 3.81 (s, 3H) 157

  3-(4-Hydroxymethyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.24, 301, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.15 (s, 1H), 9.11-9.08 (m, 2H), 9.02 (s, 1H), 7.86-7.84 (d, J= 8.4 Hz, 2H), 7.57-7.55 (d, J = 8.4 Hz, 2H), 5.35-5.20 (s, 1H), 4.65(s, 2H) 158

  3-(3-Chloro-4-fluoro-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.24, 317, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.11 (s, 1H), 9.03-9.02 (m, 2H), 8.88 (s, 1H), 8.06-8.03 (m,1H), 7.84-7.81 (m, 1H), 7.61-7.56 (m, 1H) 159

  N-[2-(6-Cyano-9H-dipyrido[2,3- b;4′,3′-d]pyrrol-3-yl)-phenyl]-acetamide C Preparative HPLC 1.22, 328, C (DMSO-D₆, 400 MHz): 13.01 (s,1H), 9.46 (s, 1H), 9.12 (s, 1H), 9.05 (s, 1H), 8.85 (s, 1H), 8.71 (s,1H), 7.70-7.65 (m, 1H), 7.53-7.45 (m, 2H), 7.42-7.39 (m, 1H), 1.93 (s,3H) 160

  3-Thiophen-2-yl-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile CWashing with THF and methanol 1.46, 277, C (DMSO-D₆, 400 MHz): 13.13 (s,1H), 9.23-9.21 (m, 3H), 9.19-9.15 (m, 1H), 7.81-7.80 (m, 2H), 7.39-7.37(m, 1H) 161

  3-(2-Chloro-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrileC Washing with THF and methanol 1.33, 305, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.85 (s, 1H), 8.72 (s, 1H),7.63-7.16 (m, 1H), 7.54-7.61 (m, 1H), 7.48-7.45 (m, 2H) 162

  3-(3-Chloro-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Washing with THF and methanol 1.28, 305, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.12 (s, 1H), 9.02-9.01 (m, 2H), 8.88 (s, 1H), 7.87 (s, 1H),7.78-7.76 (m 1H), 7.56- 7.52 (m, 1H), 7.47-7.45 (m, 1H) 163

  3-(3-Fluoro-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Washing with methanol 1.31, 289, C (DMSO-D₆, 400 MHz): 13.09 (s, 1H),9.02 (s, 1H), 8.95-8.94 (m, 2H), 8.84 (s, 1H), 7.82-7.81 (m, 2H),7.69-7.60 (m, 1H), 7.42-7.39 (m, 1H) 164

  3-(3-Trifluoromethoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.57, 355, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.14 (s, 1H), 9.04-9.02 (m, 2H), 8.90 (s, 1H), 7.79 (s, 1H),7.68-7.67 (m, 1H), 7.65- 7.63 (m, 1H), 7.73-7.41 (m, 1H) 165

  3-(4-Chloro-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Washing with THF and methanol 1.57, 305, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.07 (s, 1H), 9.01-8.99 (m, 2H), 8.90 (s, 1H), 7.82-7.80 (d, J= 8.4 Hz, 2H), 7.59-7.57 (d, J = 8.4 Hz, 2H) 166

  3-(3-Aminophenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrile CWashing with methanol 0.83, 286, C (DMSO-D₆, 400 MHz): 13.01 (s, 1H),9.07-9.03 (m, 2H), 8.95-8.94 (m, 2H), 7.82-7.80 (m, 1H), 7.75 (s, 1H),7.66-7.62 (s, 1H), 7.40-7.44 (m, 1H) 167

  3-(4-Cyano-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrile CWashing with methanol and DMF 1.12, 296, C (DMSO-D₆, 400 MHz): 13.18 (s,1H), 9.34 (s, 1H), 9.24 (s, 1H), 9.19 (s, 1H), 9.06 (s, 1H), 8.20-8.15(m, 4H) 168

  3-(4-Hydroxy-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileC Washing with methanol 1.13, 287, C (DMSO-D₆, 400 MHz): 12.80 (s, 1H),8.99 (s, 1H), 8.94 (s, 1H), 8.89 (s, 2H), 7.60-7.57 (d, J = 8.4 Hz, 2H),6.90-6.88 (d, J = 8.8 Hz, 2H) 169

  3-(3-Cyano-phenyl)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrile CWashing with methanol and DMF none (DMSO-D₆, 400 MHz): 13.10 (s, 1H),9.32 (s, 1H), 9.26-9.22 (m, 2H), 9.03 (s, 1H), 8.47 (s, 1H), 8.33-8.31(m, 1H), 8.06- 8.03 (m, 1H), 7.98-7.88 (m, 1H) 170

  3-(3-Trifluoromethyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Precipitate from DMF 1.39, 339, C (DMSO-D₆, 400 MHz):12.96 (s, 1H), 9.21 (s, 1H), 9.10 (s, 1H), 9.04 (s, 1H), 8.94 (s, 1H),8.15 (s, 2H), 7.79 (s, 2H) 171

  3-(2-Fluoro-5-hydroxymethyl- phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 1.30, 319, C (DMSO-D₆, 400MHz): 12.96 (s, 1H), 9.02 (s, 1H), 8.96 (s, 2H), 8.83 (s, 1H), 7.61-7.51(m, 1H), 7.40-7.32 (m, 2H), 5.31- 5.28 (m, 1H), 4.55-4.54 (d, J = 5.6Hz, 2H) 172

  3-(2-Methylsulfanyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.34, 317, C (DMSO-D₆, 400 MHz):12.96 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H), 8.91 (s, 1H), 8.78 (s, 1H),8.64 (s, 1H), 7.49-7.38 (m, 2H), 7.35-7.25 (m, 2H), 2.38 (s, 3H) 173

  3-(3-Fluoro-4-methoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol and DMF 1.50, 319, C (DMSO-D₆, 400MHz): 12.89 (s, 1H), 9.05 (s, 1H), 9.02-8.99 (m, 2H), 8.89 (s, 1H),7.73-7.69 (m, 1H), 7.61-7.59 (d, J = 8.4 Hz, 1H), 7.35-7.30 (m, 1H),3.90 (s, 3H) 174

  3-(2,4-Difluoro-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol then further purified bypreparative HPLC 1.32, 307, C (DMSO-D₆, 400 MHz): 12.96 (s, 1H), 9.02(s, 1H), 8.93 (s, 2H), 8.81 (s, 1H), 7.74-7.68 (m, 1H), 7.47-7.41 (m,1H), 7.28- 7.24 (m, 1H) 175

  3-(4-Chloro-3-fluoro-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol and DMF 1.41, 323/ 325, C (DMSO-D₆,400 MHz): 12.96 (s, 1H), 9.13 (s, 1H), 9.04-9.01 (m, 2H), 8.87 (s, 1H),7.91-7.81 (m, 1H), 7.73-7.68 (m, 2H) 176

  3-(3,4-Dimethoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol and DMF 1.11. 331, C (DMSO-D₆, 400MHz): 12.96 (s, 1H), 9.02-8.97 (m, 3H), 8.88 (s, 1H), 7.36-7.32 (m, 1H),7.30-7.27 (m, 1H), 7.08-7.06 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 3.78 (s,3H) 177

  3-(3,5-Difluoro-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.35, 307, C (DMSO-D₆, 400 MHz):13.16 (s, 1H), 9.34 (s, 1H), 9.25 (s, 1H), 9.21 (s, 1H), 9.03 (s, 1H),7.78-7.76 (d, J = 6.8 Hz, 2H), 7.47-7.42 (m, 1H) 178

  3-(2,5-Difluoro-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.20, 307, C (DMSO-D₆, 400 MHz):12.96 (s, 1H), 9.03 (s, 1H), 9.03 (s, 1H), 8.99 (s, 1H), 8.86 (s, 1H),7.60-7.56 (m, 1H), 7.47-7.41 (m, 1H), 7.33-7.31 (m, 1H) 179

  3-(2,5-Dimethoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.29, 331, C (DMSO-D₆, 400 MHz):12.87 (s, 1H), 9.02 (s, 1H), 8.93 (s, 1H), 8.86 (s, 1H), 8.79 (s, 1H),7.11-7.09 (d, J = 9.2 Hz, 1H), 7.02-7.01 (m, 1H), 6.98-6.96 (m, 1H),3.76 (s, 3H), 3.73 (s, 3H) 181

  3-(2,3-Dimethoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.28, 331, C (DMSO-D₆, 400 MHz):12.89 (s, 1H), 9.01 (s, 1H), 8.94 (s, 1H), 8.93 (s, 1H), 8.82 (s, 1H),8.75 (s, 1H), 7.18-7.16 (m, 1H), 7.13-7.12 (m, 1H), 7.04-7.01 (m, 1H),3.84 (s, 3H), 3.54 (s, 3H) 182

  3-(2,3-Difluoro-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.32, 307, C (DMSO-D₆, 400 MHz):13.23 (s, 1H), 9.22 (s, 1H), 9.18 (s, 1H), 9.12 (s, 1H), 9.05 (s, 1H),7.69-7.67 (m, 2H), 7.55-7.54 (m, 1H) 183

  3-(2-Chloro-5-methoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol and DMF 1.24, 335, C (DMSO-D₆, 400MHz): 13.19 (s, 1H), 9.20 (s, 1H), 9.10 (s, 1H), 9.03 (s, 1H), 8.90 (s,1H), 7.70-7.68 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 7.22-7.19 (m, 1H),3.97 (s, 3H) 184

  3-(3-Fluoro-5-methyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol and DMF 1.27, 303, C (DMSO-D₆, 400MHz): 12.96 (s, 1H), 9.13 (s, 1H), 9.05 (s, 2H), 8.92 (s, 1H), 7.52 (s,1H), 7.50-7.47 (d, J = 10.4 Hz, 1H), 7.11-7.09 (d, J = 9.6 Hz, 1H), 2.44(s, 3H) 185

  3-(3-Chloro-5-methoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol and DMF 1.40, 335, C (DMSO-D₆, 400MHz): 13.11 (s, 1H), 9.32 (s, 1H), 9.22-9.19 (m, 2H), 9.02 (s, 1H), 7.63(s, 1H), 7.51 (s, 1H), 7.24 (s, 1H), 4.04 (s, 3H) 186

  N-[4-(6-Cyano-9H-dipyrido[2,3- b;4′,3′-d]pyrrol-3-yl)-phenyl]-acetamide D Preparative HPLC 0.98, 328, C (DMSO-D₆, 400 MHz): 12.92 (s,1H), 10.10 (s, 1H), 9.02 (s, 2H), 8.98 (s, 1H), 8.92 (s, 1H), 7.74 (s,4H), 2.07 (s, 3H) 187

  N-[4-(6-Cyano-9H-dipyrido[2,3- b;4′,3′-d]pyrrol-3-yl)-phenyl]-methanesulfonamide D Washing with THF and water then MeCN 1.15, 364, C(DMSO-D₆, 400 MHz): 12.89 (s, 1H), 9.88 (s, 1H), 9.01-9.00 (m, 2H), 8.96(s, 1H), 8.90 (s, 1H), 7.77-7.75 (d, J = 8.8 Hz, 2H), 7.36-7.33 (d, J =8.4, 2H), 3.02 (s, 3H) 188

  3-(3-Methanesulfonyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Washing with methanol 1.15, 349, C (DMSO-D₆, 400 MHz):13.01 (s, 1H), 9.23 (s, 1H), 9.13 (s, 1H), 9.06 (s, 1H), 8.97 (s, 1H),8.33 (s, 1H), 8.20-8.19 (d, J = 7.6 Hz, 1H), 7.98-7.96 (d, J = 8.0 Hz,1H), 7.85-7.81 (m, 1H), 3.33 (s, 3H) 189

  4-(6-Cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl)-N,N-dimethyl-benzene sulfonamide C Preparative HPLC 1.11,378, C (DMSO-D₆, 400 MHz): 13.01 (s, 1H), 9.20 (s, 1H), 9.11 (s, 1H),9.05 (s, 1H), 8.94 (s, 1H), 8.10-8.08 (d, J = 8.4 Hz, 2H), 7.91-7.89 (d,J = 8.4 Hz, 2H), 2.66 (s, 6H) 190

  3-(6-Cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl)-N,N-dimethyl-benzene sulfonamide C Preparative HPLC 1.22,378, C (DMSO-D₆, 400 MHz): 13.01 (s, 1H), 9.19 (s, 1H), 9.09 (s, 1H),9.04 (s, 1H), 8.99 (s, 1H), 8.19-8.17 (m, 1H), 8.09 (s, 1H), 7.80-7.84(m, 2H), 2.68 (s, 6H) 191

  3-(3-Fluoro-5-hydroxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.21, 305, C (DMSO-D₆, 400 MHz):12.92 (s, 1H), 9.04-9.00 (m, 1H), 9.12 (s, 1H), 8.94 (s, 1H), 8.90 (s,1H), 7.06-7.00 (m, 2H), 6.62- 6.59 (m, 1H) 192

  3-(5-Fluoro-2-hydroxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.21, 305, C (DMSO-D₆, 400 MHz):12.86 (s, 1H), 9.74 (s, 1H), 9.00 (s, 1H), 8.94-8.92 (m, 2H), 8.85 (s,1H), 7.27-7.23 (m, 1H), 7.07- 6.95 (m, 2H) 193

  3-(3-Fluoro-pyridin-4-yl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Washing with methanol 1.06, 290, C (DMSO-D₆, 400 MHz):13.15 (s, 1H), 9.14 (s, 1H), 9.07 (s, 1H), 9.00-8.99 (m, 2H), 8.78 (s,1H), 8.60 (s, 1H), 7.86-7.83 (m, 1H) 194

  3-(4-Hydroxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C Preparative HPLC 0.85, 305, C (DMSO-D₆, 400 MHz): 13.15(s, 1H), 9.61 (s, 1H), 9.05 (s, 1H), 8.97 (s, 1H), 8.87-8.86 (m, 2H),8.09 (s, 1H), 7.65-7.63 (d, J = 8.8 Hz, 2H), 7.52 (s, 1H), 6.91-6.89 (d,J = 8.8 Hz, 2H) 195

  3-(3-Isopropyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D Preparative HPLC 0.98, 313, C (DMSO-D₆, 400 MHz): 12.96(s, 1H), 9.07 (s, 1H), 9.02-8.99 (m, 2H), 8.94 (s, 1H), 7.65 (s, 1H),7.60-7.58 (d, J = 6.8 Hz, 1H), 7.46-7.42 (m, 1H), 7.30- 7.28 (d, J = 7.2Hz, 1H), 3.00- 2.97 (m, 1H), 1.28-1.27 (d, J = 6.8 Hz, 6H)

Preparative HPLC condition used in Table 8:

Autopurification system equipped with a YMC s-5μ RP column (12 μm,250×20 mm; flowrate, 15 mL/min; solvent A:0.1% TFA/water; solvent B:0.1% TFA/CH₃CN; gradient:30-60% B over 13 min; UV detector fractioncollection.

Time(min) Flowrate(mL/min) solvent A % solvent B % 0 15 30 70 12 15 6040 12.2 18 100 0 15.2 18 100 0 17 15 30 70

The compounds of the Examples in Table 9 were prepared via the generalMitsunobu methods followed by the general deprotection methods describedabove.

TABLE 9 LCMS Ex- Depro- Final R_(T), am- Mitunobu tection purificationM + H⁺, ple Structure/Name Method Method Method(s) Method ¹H NMR (ppm)196

  3-[2-(dimethylamino) ethoxy]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6carbonitrile B F I 2.70, 282, E (400 MHz, DMSO-D₆): 12.66 (s, 1H), 8.98(s, 1H), 8.85 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 2.8 Hz,1H), 4.22 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 5.8 Hz, 2H), 2.26 (s, 6H).197

  3-[3-(dimethylamino) propoxy]-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile B F I 2.79, 296, E (400 MHz, DMSO-D₆): 12.65 (s, 1H), 8.98(s, 1H), 8.87 (s, 1H), 8.45 (d, J = 2.8 Hz, 1H), 8.42 (d, J = 2.8 Hz,1H), 4.16 (t, J = 6.5 Hz, 2H), 2.41 (t, J = 7.0 Hz, 2H), 2.17 (s, 6H),1.94 (p, J = 6.8 Hz, 2H). 198

  3-(piperidin-4-yloxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B F I 6.46, 294, D 400 MHz, DMSO-D₆): 8.93 (d,J = 0.9 Hz, 1H), 8.77 (s, 1H), 8.43-8.35 (m, 2H), 4.47-4.35 (m, 1H),4.03 (m, 1H), 2.99 (dt, J = 12.9, 4.1 Hz, 2H), 2.62-2.53 (m, 1H), 1.99(m, 2H), 1.59-1.42 (m, 2H), 1.18 (m, 1H). 199

  3-(2-(ethylamino)ethoxy)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B F I 6.04, 282, D (400 MHz, DMSO-D₆): 8.99 (s,1H), 8.87 (s, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.45-8.41 (m, 1H), 4.18 (t,J = 5.6 Hz, 2H), 2.97 (t, J = 5.6 Hz, 2H), 2.64 (q, J = 7.1 Hz, 2H),1.05 (t, J = 7.1 Hz, 3H) 200

  3-(pyrrolidin-2-ylmethoxy)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B F I 2.77, 294, E (500 MHz, DMSO-D₆): 8.99 (d,J = 1.0 Hz, 1H), 8.85 (d, J = 0.9 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H),8.43 (d, J = 2.8 Hz, 1H), 8.30 (s, 1H), 4.12-4.01 (m, 2H), 3.64-3.56 (m,2H), 3.00-2.89 (m, 2H), 2.01-1.93 (m, 1H), 1.77 (m, 2H), 1.58 (m, 1H).201

  3-((S)-Pyrrolidin-3-yloxy)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B F I 2.65, 280, E (400 MHz, DMSO-D₆): 8.99 (s,1H), 8.90 (s, 1H), 8.43 (d, J = 2.8 Hz, 1H), 8.41 (d, J = 2.8 Hz, 1H),5.00 (t, J = 5.6 Hz, 1H), 3.19 (dd, J = 12.4, 5.2 Hz, 2H), 3.05-2.95 (m,2H), 2.94-2.85 (m, 1H), 2.13 (m, 1H), 1.96-1.85 (m, 1H). 202

  3-((1-methylpiperidin-4- yl)methoxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B F I 7.06, 322, D (400 MHz, DMSO-D₆): 12.65(s, 1H), 8.98 (d, J = 0.9 Hz, 1H), 8.86 (d, J = 0.9 Hz, 1H), 8.46 (d, J= 2.8 Hz, 1H), 8.43 (d, J = 2.9 Hz, 1H), 4.10-3.93 (m, 2H), 2.84 (d, J =10.1 Hz, 1H), 2.71-2.56 (m, 1H), 2.15 (s, 3H), 2.13-2.01 (m, 1H), 1.91(m, 1H), 1.81-1.71 (m, 1H), 1.66 (m, 1H), 1.60-1.43 (m, 1H), 1.24 (s,1H), 1.21- 1.06 (m, 1H). 203

  3-(piperidin-3-yloxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile B F I 6.48, 294, D (400 MHz, DMSO-D₆): 8.96 (d,J = 0.8 Hz, 1H), 8.83 (s, 1H), 8.43 (m, 2H), 4.29 (m, 1H), 3.16 (m, 1H),2.84-2.75 (m, 1H), 2.64-2.51 (m, 2H), 2.11 (s, 1H), 1.76-1.67 (m, 1H),1.51 (m, 2H). 204

  3-(2-methoxyethoxy)-9H- dipyrido[2,3-b;4′,3′- d]pyrrole-6-carbonitrileB F I 9.04, 269, D (400 MHz, DMSO-D₆): 12.66 (s, 1H), 8.98 (d, J = 0.9Hz, 1H), 8.84 (d, J = 0.9 Hz, 1H), 8.48 (d, J = 2.9 Hz, 1H), 8.42 (d, J= 2.9 Hz, 1H), 4.29-4.23 (m, 2H), 3.75 (m, 2H), 3.35 (s, 3H). 205

  3-ethoxy-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6- carbonitrile B F I10.53, 239, D (400 MHz, DMSO-D₆): 8.96 (d, J = 0.9 Hz, 1H), 8.82 (d, J =0.9 Hz, 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.37 (d, J = 2.9 Hz, 1H), 4.19(q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H).

Example 2063-(2,3-Dihydroindol-1-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:3-(2,3-Dihydro-indol-1-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Indoline (67 mg, 0.56 mmol) was added to a solution of3-bromo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(210 mg, 0.52 mmol), tribasic potassium phosphate (164 mg, 0.77 mmol)and dicyclohexyl-(2′,6′-diisopropoxy-biphenyl-2-yl)-phosphane (88 mg,0.19 mmol) in anhydrous toluene (5.0 mL). The reaction mixture wasdegassed with nitrogen for 10 minutes, heated at 110° C. for 18 h andthen allowed to cool to ambient temperature. The resultant mixture waspoured into water (40 mL) and extracted with DCM (2×40 mL). The combinedorganic phase was separated, dried over anhydrous sodium sulfate,filtered and evaporated in vacuo. The resultant residue was purified byflash chromatography (silica, 12 g column, ISCO, 0-40% ethyl acetate incyclohexane) and the isolated solid triturated with diethylether/pentaneand air dried to afford the title compound as a yellow powder (124 mg,54%). LCMS (Method B): R_(T)=4.83 min, M+H⁺=442.

Step 2:3-(2,3-Dihydroindol-1-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

3-(2,3-Dihydroindol-1-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(124 mg) was subjected to general deprotection Method A. The resultantresidue was purified by flash chromatography (silica, 40 g column, ISCO,0-20% MeOH in DCM), then HPLC (20-90% MeCN over 30 min, 15 mL/min) toafford the title compound as an orange solid (10.5 mg). ¹H NMR (DMSO-D₆,400 MHz): 12.70 (s, 1H), 9.00 (d, J=1.1 Hz, 1H), 8.96 (d, J=1.1 Hz, 1H),8.72 (d, J=2.7 Hz, 1H), 8.70 (d, J=2.7 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H),7.11-7.01 (m, 2H), 6.76 (td, J=7.1, 1.4 Hz, 1H), 4.05 (t, J=8.4 Hz, 2H),3.17 (t, J=8.4 Hz, 2H). LCMS (Method A): R_(T)=10.52 min, M+H⁺=311.

Example 2073-[4-(8-Aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1: 8-(4-Bromobenzyl)-8-aza-bicyclo[3.2.1]octan-3-one

A stirred solution of 1-bromo-4-bromomethylbenzene (0.39 g, 1.56 mmol),triethylamine (0.45 mL, 3.20 mmol) and 8-azabicyclo[3.2.1]octan-3-one(0.33 mL, 2.32 mmol) in THF (10 mL) was heated under reflux for 5 h. Thereaction mixture was allowed to cool to ambient temperature and thesolid removed by filtration. The filtrate was concentrated under reducedpressure to afford a residue that was purified by flash chromatography(silica, 50 g column, Biotage, 0-100% DCM in ethyl acetate) to affordthe title compound as an off-white solid (400 mg, 90%). ¹H NMR (CDCl₃,300 MHz): 7.48-7.43 (m, 2H), 7.32-7.28 (m, 2H), 3.69 (s, 2H), 3.49-3.43(m, 2H), 2.66 (dd, J=16.0, 4.3 Hz, 2H), 2.26-2.17 (m, 2H), 2.14-2.06 (m,2H), 1.66-1.56 (s, 2H). LCMS (Method B): R_(T)=1.86 min, M+H⁺=294/296.

Step 2: 8-(4-Bromobenzyl)-8-aza-bicyclo[3.2.1]octan-3-ol

Sodium borohydride (95 mg, 1.50 mmol) was added to a solution of8-(4-bromobenzyl)-8-azabicyclo-[3.2.1]octan-3-one (0.22 g, 0.75 mmol) inmethanol (10 mL) and the reaction mixture was stirred for 30 minutes.The reaction was diluted with water (10 mL) and extracted into DCM (3×20mL). The combined organic layer was washed with saturated aqueous sodiumbicarbonate solution (10 mL), dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to afford the title compound as anoff-white solid (200 mg, 90%). ¹H NMR (CDCl₃, 300 MHz): 7.43 (dd, J=8.3,2.0 Hz, 3H), 7.29-7.23 (m, 2H), 3.60-3.45 (m, 2H), 3.23-3.10 (m, 2H),2.16-1.40 (m, 8H). LCMS (Method B): R_(T)=1.90 min, M+H⁺=296/298.

Step 3:3-[4-(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A degassed mixture of3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(217 mg, 0.48 mmol), 8-(4-bromobenzyl)-8-aza-bicyclo[3.2.1]octan-3-ol(157 mg, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (33 mg, 5mol %) and cesium carbonate (157 mg, 0.48 mmol) in a mixture of DME (5mL), IMS (2 mL) and water (1.3 mL) was heated under microwaveirradiation at 100° C. for 30 minutes. The cooled reaction mixture waspurified by flash chromatography (silica, 50 g column, Biotage, 0-5% (2Nammonia in MeOH) in DCM) to afford the title compound as an off-whitesolid (155 mg, 60%). ¹H NMR (CDCl₃, 300 MHz): 9.21-9.17 (m, 1H), 8.95(d, J=2.1 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.43 (s, 1H), 7.67-7.53 (m,4H), 6.04 (s, 2H), 3.70-3.58 (m, 4H), 3.35-3.15 (m, 2H), 2.20-1.60 (m,10H), 0.95 (t, J=8.2 Hz, 2H), 0.00 (s, 9H). LCMS (Method B): R_(T)=2.92min, M+H⁺=540.

Step 4: Imidazole-1-carbothioic acidO-(8-{4-[6-cyano-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl]-benzyl}-8-aza-bicyclo[3.2.1]oct-3-yl)ester

A solution of3-[4-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(155 mg, 0.29 mmol), DMAP (5 mg, catalytic) andN,N′-thiocarbonyldiimidazole (455 mg, 8.76 mmol) in DCM (10 mL) washeated under reflux for 12 h. The cooled reaction mixture was purifiedby flash chromatography (silica, 50 g column, Biotage, 0-5% MeOH in DCM)to afford the title compound as a white solid (182 mg, 97%). NMR (CDCl₃,300 MHz): 9.28-9.25 (m, 1H), 9.04 (dd, J=7.0, 2.2 Hz, 1H), 8.69-8.66 (m,1H), 8.51 (d, J=1.0 Hz, 1H), 8.47-8.39 (m, 1H), 7.81-7.61 (m, 5H),7.15-7.10 (m, 1H), 6.12 (s, 2H), 4.35 (s, 2H), 3.76-3.61 (m, 4H),2.32-2.17 (m, 4H), 2.13-1.93 (m, 5H), 1.08-0.96 (m, 2H), 0.00 (s, LCMS(Method B): R_(T)=3.13 min, M+H⁺=650.

Step 5:3-[[4-(8-Aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

To a solution of imidazole-1-carbothioic acidO-(8-{4-[6-cyano-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-3-yl]-benzyl}-8-aza-bicyclo[3.2.1]oct-3-yl)ester (182 mg, 0.28 mmol) and AIBN (60 mg, 0.36 mmol) in toluene (10 mL)under an argon atmosphere was added tributyltin hydride (0.58 mL, 1.85mmol). On complete addition, the reaction was heated at 110° C. for 15minutes then allowed to cool to ambient temperature. The mixture wasconcentrated in vacuo and the resultant residue was purified by flashchromatography (silica, 50 g column, Biotage, 0-5% MeOH in DCM) toafford the title compound as a white solid (123 mg, 84%). ¹H NMR (CDCl₃,300 MHz): 9.26 (d, J=1.0 Hz, 1H), 9.03 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2Hz, 1H), 8.51 (d, J=1.0 Hz, 1H), 7.72-7.60 (m, 4H), 6.12 (s, 2H),3.74-3.65 (m, 4H), 3.37-3.22 (m, 2H), 2.16-1.40 (m, 10H), 1.06-0.97 (m,2H), 0.00 (s, 9H). LCMS (Method B): R_(T)=2.96 min, M+H⁺=524.

Step 6:3-[4-(3-Hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of3-[4-(8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(120 mg, 0.23 mmol) in TBAF (1N in THF, 3 mL) and the reaction mixturewas heated at 55° C. for 16 h. The mixture was then concentrated invacuo and the resultant residue purified by flash column chromatography(silica, 50 g column, Biotage, 0-20% MeOH in DCM) to afford the titlecompound as an off-white solid (85 mg, 94%). ¹H NMR (CDCl₃, 300 MHz):9.01 (d, J=1.0 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H),8.49 (d, J=1.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.58-7.51 (m, 2H),3.64-3.57 (m, 2H), 3.39-3.37 (m, 2H), 2.11-2.04 (m, 2H), 1.90-1.72 (m,2H), 1.68-1.33 (m, 6H). LCMS (Method A): R_(T)=6.31 min, M+H⁺=394.

Example 2086-Cyano-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-N-oxide

A mixture of6-cyano-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(110 mg, 0.30 mmol) and 3-phenyl-2-(phenylsulfonyl)oxaziridine (102 mg,0.39 mmol) in DCM (5.8 mL) was stirred at room temperature for 2 h. Thesolid was collected by filtration and washed with DCM (3×20 mL) toafford a bright yellow solid (100 mg, 90%). ¹H NMR (400 MHz, DMSO-D₆):8.98 (s, 1H), 8.91 (s, 1H), 8.90 (s, 1H), 8.83 (s, 1H), 7.66 (m, 4H),4.43 (s, 2H), 3.13 (m, 2H), 2.14 (m, 2H), 1.59 (m, 4H), 1.34 (m, 2H).LCMS (method D): R_(T)=8.82 min, M+H⁺=384.

Example 2093-[4-(1-Ethyl-piperidin-2-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1: 2-(4-Bromophenyl)pyridine

1,4-Dibromobenzene (5.90 g, 25.0 mmol) was dissolved in anhydrousdiethyl ether (40 mL) and flushed with argon before the solution wascooled to −78° C. and n-butyl lithium (2.5M in hexanes, 10.2 mL, 25.6mmol) was added dropwise at a rate that maintained the temperature below−70° C. The reaction mixture was stirred at this temperature for 30minutes then 2-fluoropyridine (1.72 mL, 20.0 mmol) was added dropwiseand stirring continued at −78° C. for 1 h then the reaction mixture wasallowed to warm to room temperature and stirred for 1 h. The reactionmixture was poured onto water (50 mL) and extracted with diethyl ether(3×50 mL). The combined organic layers were washed with 5% HCl (3×200mL) then the pH of the aqueous phase was adjusted to 10 by the additionof potassium hydroxide and the aqueous phase was extracted with diethylether (3×200 mL). The combined organic phase was dried over sodiumsulfate, filtered and evaporated to afford the title compound (2.7 g,58%). NMR (CDCl₃, 300 MHz): 8.71-8.66 (m, 1H), 7.91-7.85 (m, 2H),7.79-7.67 (m, 2H), 7.64-7.57 (m, 2H), 7.28-7.22 (m, 1H).

Step 2: 2-(4-Bromophenyl)-1-ethyl-1,2,3,6-tetrahydropyridine

To a solution of 2-(4-bromophenyl)pyridine (2.7 g, 11.5 mmol) in DMF (50mL) was added ethyl iodide (1.9 mL, 23.1 mmol) and the reaction mixturewas heated to 80° C. for 16 h. The mixture was cooled then evaporatedand the resultant residue dissolved in methanol (100 mL) before additionof sodium borohydride (1.5 g, 39.2 mmol) portionwise. The reactionmixture was stirred at ambient temperature for 1 h then evaporated andsaturated aqueous sodium carbonate solution was added. The mixture wasextracted with ethyl acetate (2×100 mL). The combined organic layer wasdried over sodium sulfate, filtered and evaporated then the residue waspurified by flash chromatography (silica, Biotage 100 g column, 50%ethyl acetate in cyclohexane) to afford the title compound (0.9 g, 29%),which was used without further purification. ¹H NMR (CDCl₃, 300 MHz):7.47-7.42 (m, 2H), 7.24-7.19 (m, 2H), 5.86-5.74 (m, 2H), 3.47-3.35 (m,2H), 2.98-2.87 (m, 1H), 2.64-2.46 (m, 1H), 2.33-2.26 (m, 2H), 2.13-2.00(m, 1H), 0.99 (t, J=7.2 Hz, 3H).

Step 3:3-[4-(1-Ethylpiperidin-2-yl)-phenyl]-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A degassed mixture of2-(4-bromophenyl)-1-ethyl-1,2,3,6-tetrahydropyridine (0.13 g, 0.49mmol), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(0.20 g, 0.44 mmol), cesium carbonate (0.15 g) andtetrakis(triphenylphosphine)palladium(0) (30 mg) in DME (5 mL), IMS (2mL) and water (1.3 mL) was heated under microwave irradiation at 140° C.for 30 minutes. The reaction mixture was allowed to cool to ambienttemperature then purified by flash chromatography (silica, Biotage 50 gcolumn, 0-100% (5% methanol in DCM)) to afford a colurless residue (95mg). The resultant residue was dissolved in IMS (10 mL) and the flaskdegassed with nitrogen. Palladium on carbon (10% by wt., 11 mg) wasadded and the reaction mixture placed under an atmosphere of hydrogenand stirred for 16 h. The solid was removed by filtration and thefiltrate evaporated to afford the title compound (85 mg) which was usedwithout further purification. ¹H NMR (CHCl₃, 400 MHz,): 9.18 (d, J=1.0Hz, 1H), 8.95 (d, J=2.2 Hz, 1H), 8.61 (d, J=2.2 Hz, 1H), 8.42 (d, J=1.0Hz, 1H), 7.68-7.61 (m, 2H), 7.60-7.53 (m, 2H), 6.04 (s, 2H), 3.67-3.59(m, 2H), 3.40-3.20 (m, 2H), 2.79-2.67 (m, 1H), 2.37-2.16 (m, 2H),1.93-1.73 (m, 4H), 1.46-1.35 (m, 2H), 1.34-1.20 (m, 2H), 1.05-0.78 (m,3H), −0.07 (s, 9H).

Step 4:3-[4-(1-Ethylpiperidin-2-yl)-phenyl]-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile

A solution of3-[4-(1-ethyl-piperidin-2-yl)-phenyl]-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (75 mg, 0.147mmol) in TBAF (1M in THF, 1.5 mL, 1.47 mmol) was heated at 55° C. for 16h. The reaction mixture was concentrated in vacuo and the resultantresidue was partitioned between water and ethyl acetate. The organiclayer was separated, dried over sodium sulfate, filtered and evaporatedto give a yellow solid. The resultanat solid was purified by flashchromatography (silica, Biotage 50 g column, 0-100% (10% methanol inDCM)) to afford the title compound (11 mg, 20%). ¹H NMR (DMSO-D₆, 400MHz): 12.89 (s, 1H), 9.08 (d, J=2.3 Hz, 1H), 9.04 (d, J=1.1 Hz, 1H),9.02 (d, J=2.3 Hz, 1H), 8.93 (d, J=1.1 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H),7.49 (d, J=8.0 Hz, 2H), 3.16-3.07 (m, 2H), 2.54-2.42 (m, 1H), 2.11-1.93(m, 2H), 1.79-1.64 (m, 3H), 1.63-1.20 (m, 3H), 0.89 (t, J=7.1 Hz, 3H).LCMS (Method A): R_(T)=6.23 min; M+H⁺=382

Example 2103-(Oxazol-2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(101 mg, 0.369 mmol) and lithium chloride (46.9 mg, 1.11 mmol) in DMF(0.63 mL) was treated with DIPEA (161 μL, 0.922 mmol) and2-(tri-n-butylstannyl)oxazole (232 μL, 1.11 mmol), and then degassed bythe bubbling of nitrogen for 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (21.3 mg, 18.4 μmol, 5.0 mol %)was added and the mixture heated at 165° C. for 15 hours. The mixturewas allowed to cool and treated with saturated aqueous potassiumfluoride solution at ambient temperature. The resulting solids wereremoved by filtration and washed with 20% methanol in DCM and water. Thefiltrate was filtered through a pad of celite, washing with 20% methanolin DCM. The layers were separated, the aqueous phase extracted into 20%methanol in DCM, and the combined organic phases concentrated in vacuo.The residue was dissolved in AcOH with sonication and heating, filteredhot, and allowed to cool. The resulting suspension was treated withwater and then filtered to collect the tan-gray solid, which wasredissolved in DMF and purified by preparative HPLC [2-60% MeCN/watermodified with 0.1% ammonium hydroxide] to afford a tan solid (43.5 mg,45%). ¹H NMR (400 MHz, DMSO-D₆): 9.29 (d, J=2.2 Hz, 1H), 9.26 (d, J=2.2Hz, 1H), 9.03 (m, 1H), 8.97 (m, 1H), 8.28 (m, 1H), 7.43 (m, 1H). LCMS(Method D): R_(T)=8.29 min, M+H⁺=262.

Example 2113-(Thiazol-2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(100 mg, 0.366 mmol) and lithium chloride (46.6 mg, 1.10 mmol) in DMF(0.63 mL) was treated with DIPEA (159 uL, 0.915 mmol) and2-(tri-n-butylstannyl)thiazole (345 uL, 1.10 mmol), and then degassed bythe bubbling of nitrogen for 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (21.2 mg, 18.3 umol, 5.0 mol %)was added and the mixture heated at 165° C. for 15 hours. The mixturewas allowed to cool and treated with saturated aqueous potassiumfluoride solution at ambient temperature. The resulting solids wereremoved by filtration and washed with 20% methanol in DCM and water. Thefiltrate was filtered through a pad of celite, washing with 20% methanolin DCM. The layers were separated, the aqueous phase extracted into 20%methanol in DCM, and the combined organic phases concentrated in vacuo.The residue was dissolved in AcOH with sonication and heating, filteredhot and allowed to cool. The resulting suspension was treated with waterand then filtered to collect the off-white solid. This solid waspurified by preparative HPLC [0-30% MeCN/water modified with 0.1% formicacid] to afford an off-white solid powder (5.0 mg, 18%). ¹H NMR (400MHz, DMSO-D₆): 9.26 (s, 1H), 9.24 (s, 1H), 9.01 (s, 1H), 8.94 (s, 1H),7.96 (d, J=3.2 Hz, 1H), 7.80 (d, J=3.2 Hz, 1H). LCMS (Method D):R_(T)=9.31 min, M+H⁺=278.

Example 2123-Ethylamino-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:3-(tert-Butylcarbonyl)ethylamino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

To a solution of3-tert-butyl-carbonylamino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(108 mg, 0.25 mmol) in THF (2.0 mL) was added sodium hydride (14.2 mg,0.59 mmol). After the bubbling had ceased, iodoethane (47.3 μL, 0.592mmol) was added and the reaction mixture heated at 55° C. overnight. Thecooled reaction mixture was diluted with water and EtOAc, the layersseparated, and the aqueous phase extracted into EtOAc. The combinedorganic phase was dried over sodium sulfate, filtered, and concentratedin vacuo. The resultant residue was dissolved in EtOAc and absorbed ontosilica gel for purification by flash chromatography (silica, 12 gcolumn, Biotage, 1-50% EtOAc in heptane) to afford the title compound asa viscous yellow oil (96 mg, 83%).

Step 2: 3-ethylamino-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of3-(tert-butylcarbonyl)ethylamino-9-(2-trimethylsilanyl-ethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(161 mg, 0.345 mmol) in 1,4-dioxane (500 μL) was treated with 48%aqueous hydrobromic acid (500 μL) and heated at 75° C. for 10 min. Thecooled reaction mixture was basified to pH 12 with 6N aqueous sodiumhydroxide solution and then adjusted to pH 7-9 with dropwise addition of1N hydrochloric acid. The solid was collected via centrifugation, theaqueous supernate discarded, and the solid dissolved in 1-2 mL of DMSOand purified by preparative HPLC (5-85% MeCN in water (0.1% NH₄OH) over30 min, 35 mL/min) to afford the title compound as a yellow solid (22mg, 26%). ¹H NMR (DMSO-D₆, 500 MHz): 8.89 (d, J=1.0 Hz, 1H), 8.78 (d,J=0.9 Hz, 1H), 8.22 (d, J=2.7 Hz, 1H), 7.78 (d, J=2.7 Hz, 1H), 5.76 (t,J=5.5 Hz, 1H), 3.20-3.07 (m, 2H), 1.25 (t, J=7.1 Hz, 3H). LCMS (MethodE): R_(T)=2.69 min, M+H⁺=238.1.

Example 2133(1-Pyrrolidinylcarbonylamino)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1: 3-Amino-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of3-tert-butyl-carbonylamino-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(101 mg, 0.229 mmol) in 1,4-dioxane (1.0 mL) was treated with a solutionof 4M HCl in 1,4-dioxane (6 mL). After 1 h, an additional portion of4.0M HCl in 1,4-dioxane (1.5 mL) was added to the reaction mixture.After 4.5 h at ambient temperature, the solvent was evaporated to affordan orange solid (70 mg, quantitative yield). The solid was used withoutpurification.

Step 2:3-(1-Pyrrolidinylcarbonylamino)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of 3-amino-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(47.9 mg, 0.229 mmol) in pyridine (6.1 mL) was treated withpyrrolidine-1-carbonyl chloride (83.4 μL, 0.755 mmol) and heated at 60°C. for 4 h. The cooled reaction mixture was treated with saturatedaqueous sodium bicarbonate solution then diluted with 20% MeOH in DCMand water. The layers were separated, the aqueous phase extracted with20% MeOH in DCM, and the combined organic phase was dried over sodiumsulfate and concentrated in vacuo. The resultant residue was dissolvedin DCM/methanol, absorbed onto silica gel, and purified by flashchromatography (silica, 4 g column, Biotage, 1-20% methanol in DCMcontaining 0.1% 7N ammonia in MeOH). Collecting appropriate fractionsafforded a yellow solid which was further purified by preparative HPLC(5-85% MeCN in water (0.1% NH₄OH) over 30 min, 35 mL/min) to afford thetitle compound as an off-white solid (8.0 mg, 11%). ¹H NMR (400 MHz,DMSO-D₆): 12.92 (s, 1H), 8.78 (s, 1H), 8.70 (dd, J=4.7, 1.4 Hz, 1H),8.60 (dd, J=7.9, 1.4 Hz, 1H), 7.47 (dd, J=7.9, 4.8 Hz, 1H), 4.71 (dd,J=8.7, 4.6 Hz, 1H), 2.85 (m, 2H), 2.07 (m, 4H), 1.92 (m, 2H). LCMS(Method E): R_(T)=3.36 min, M+H⁺=307.

Example 214 3-Chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of3-chloro-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(24.2 mg, 67.4 μmol) in THF (1.3 mL) was treated with TBAF (398 μL, 1.35mmol) and heated to 60° C. for 2 h. The reaction mixture was cooled toambient temperature and the solvent removed in vacuo. The resultantresidue was dissolved in DCM/EtOAc, absorbed onto silica gel, andpurified by flash chromatography (silica, 4 g column, Biotage, 1-20%methanol in DCM containing 0 1% 7N ammonia in MeOH). Collectingappropriate fractions afforded a solid which was further purified bypreparative HPLC (5-85% MeCN in water (0.1% NH₄OH) over 30 min, 35mL/min) to afford the title compound as an off-white solid (10 mg, 66%).NMR (400 MHz, DMSO-D₆): 13.07 (s, 1H), 9.05 (d, J=0.9 Hz, 1H), 8.95 (d,J=2.4 Hz, 1H), 8.92 (d, J=0.9 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H). LCMS(Method E): R_(T)=3.98 min, M+H⁺=229.

Example 2153-(3-Hydroxy-3-methylbut-1-ynyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:3-(3-Hydroxy-3-methylbut-1-ynyl)-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

In a flame dried flask, a mixture of3-bromo-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(203 mg, 0.503 mmol) and copper (I) iodide (9.58 mg, 50.3 μmol) in1,4-dioxane (5.3 mL) was degassed and flushed with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (58.1 mg, 50.3 μmol) and2-methyl-3-butyn-2-ol (244 μL, 2.52 mmol) were added and the reactionmixture was degassed, purged with nitrogen, and heated at 105° C. for 70min. The cooled reaction mixture was diluted with DCM and water, thelayers separated, and the aqueous phase extracted into DCM. The combinedorganic phase was dried over sodium sulfate and concentrated in vacuo.The resultant residue was dissolved in EtOAc and absorbed onto silicagel for purification by flash chromatography (silica, 25 g column,Biotage, 1-100% EtOAc in heptane) to afford further title compound as awhite-yellow solid (254 mg, 124%). The solid was used without furtherpurification. ¹H NMR (DMSO-D₆, 400 MHz,): 9.33 (s, 1H), 8.98 (s, 1H),8.91 (d, J=1.9 Hz, 1H), 8.76 (d, J=1.9 Hz, 1H), 6.03 (s, 2H), 5.55 (s,1H), 3.57 (t, J=7.9 Hz, 2H), 1.51 (s, 6H), 0.82 (t, J=8.0 Hz, 2H), −0.16(s, 9H).

Step 2:3-(3-Hydroxy-3-methylbut-1-ynyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of3-(3-hydroxy-3-methylbut-1-ynyl)-9-(2-trimethylsilanyl-ethoxymethyl)dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(254 mg, 0.624 mmol) in THF (12 mL) was treated with TBAF (3.7 mL, 12.5mmol) and heated to 60° C. for 24 h. The reaction mixture was allowed tocool to ambient temperature and the solvent removed in vacuo. Theresultant residue was dissolved in DCM, absorbed onto silica gel, andpurified by flash chromatography (Biotage, 25 g, 1-100% EtOAc inhepatne). The light orange solid was further purified by preparativeHPLC (5-85% MeCN in water (0.1% NH₄OH) over 30 min, 35 mL/min) to affordthe title compound as an off-white solid (21 mg, 12%). ¹H NMR (DMSO-D₆,400 MHz,): 12.99 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H), 8.86 (d, J=2.0 Hz,1H), 8.69 (d, J=2.0 Hz, 1H), 5.53 (s, 1H), 1.55 (s, 6H). LCMS (MethodD): R_(T)=9.66 min, M+H⁺=277.

Example 216 3-Hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of3-hydroxy-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,31-d]pyrrole-6-carbonitrile(90.9 mg, 0.267 mmol) in 1,4-dioxane (500 μL) was treated with 48%aqueous hydrobromic acid (500 μL) and heated at 75° C. for 10 min. Thecooled reaction mixture was basified to pH 12 with 6N aqueous sodiumhydroxide solution and then adjusted to pH 7-9 with dropwise addition of1N hydrochloric acid. The solid was collected via centrifugation, theaqueous supernate discarded, and the solid dissolved in 1-2 mL of DMSOand purified by preparative HPLC (0-30% MeCN in water (0.1% formic acid)over 30 min, 35 mL/min) to afford the title compound as an off-whitesolid (19 mg, 33%). ¹H NMR (DMSO-D₆, 400 MHz,): 12.51 (s, 1H), 9.94 (s,1H), 8.94 (s, 1H), 8.87 (s, 1H), 8.32 (d, J=2.7 Hz, 1H), 8.08 (d, J=2.7Hz, 1H). LCMS (Method E): R_(T)=2.90 min, M+H⁺=211.

Example 2173-(Pyridin-2-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(150 mg, 0.549 mmol) and lithium chloride (69.9 mg, 1.65 mmol) in DMF(0.94 mL) was treated with DIPEA (239 μL, 1.37 mmol) and2-(tributylstannyl)pyridine (607 μL, 1.65 mmol), and then degassed bythe bubbling of nitrogen for 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (31.7 mg, 27.5 μmol, 5.0 mol %)was added and the mixture heated at 165° C. for 15 h. The mixture wasallowed to cool and treated with saturated aqueous potassium fluoride atambient temperature. The resulting solids were removed by filtration andwashed with 20% methanol in DCM and water. The filtrate was filteredthrough a pad of celite, washing with 20% methanol in DCM. The layerswere separated, the aqueous phase extracted into 20% methanol in DCM,and the combined organic phases concentrated in vacuo to afford a solidresidue. This solid was purified by preparative HPLC (0-30% MeCN/watermodified with 0.1% formic acid) to afford an off-white solid powder (8.9mg, 6.0%). ¹H NMR (DMSO-D₆, 400 MHz,): 13.01 (s, 1H), 9.49 (d, J=2.2 Hz,1H), 9.43 (d, J=2.2 Hz, 1H), 9.04 (dd, J=11.6, 0.8 Hz, 2H), 8.75 (d,J=4.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.98 (td, J=7.8, 1.8 Hz, 1H),7.43 (dd, J=6.7, 4.9 Hz, 1H). LCMS (Method D): R_(T)=7.26 min, M+H⁺=272.

Compounds of the Examples in Table 10 were made via procedures describedabove using appropriate starting materials, reagents and following theprocedures outlined in the general methods.

TABLE 10 Ex- General General Final LCMS R_(T), am- AkylationDeprotection purification M + H⁺, ple Structure/Name Method MethodMethod(s) Method ¹H NMR (ppm) 218

  4-(Piperidin-4-yloxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 5.67, 294, D (DMSO-D₆, 400 MHz): 8.97 (s, 1H), 8.52(d, J = 5.8 Hz, 1H), 8.47 (s, 1H), 7.10 (d, J = 5.9 Hz, 1H), 4.95 (m,1H), 3.11-3.03 (m, 2H), 2.76 (m, 2H), 2.08 (m, 2H), 1.88- 1.67 (m, 2H).219

  4-[2-(diethylamino)ethoxy]- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 6.00, 310, D (DMSO-D₆, 400 MHz): 12.76(s, 1H), 8.97 (s, 1H), 8.55 (d, J = 5.7 Hz, 1H), 8.50 (s, 1H), 7.06 (d,J = 5.8 Hz, 1H), 4.41 (t, J = 5.5 Hz, 2H), 3.02 (s, 2H), 2.65 (d, J =6.8 Hz, 4H), 1.04 (t, J = 7.1 Hz, 6H). 220

  4-(2-(ethylamino)ethoxy]-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 5.68, 282, D (DMSO-D₆, 400 MHz): 8.97 (s, 1H), 8.57(s, 1H), 8.54 (d, J = 5.7 Hz, 1H), 8.28 (s, 1H), 7.05 (d, J = 5.8 Hz,1H), 4.41 (t, J = 5.5 Hz, 2H), 3.13 (t, J = 5.6 Hz, 2H), 2.72 (q, J =7.1 Hz, 2H), 1.08 (t, J = 7.1 Hz, 3H). 221

  (R)-4-(Pyrrolidin-2- ylmethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 5.94, 294, D (DMSO-D₆, 400 MHz):8.98 (s, 1H), 8.63 (s, 1H), 8.56 (d, J = 5.7 Hz, 1H), 7.06 (d, J = 5.8Hz, 1H), 4.41 (m, 4.4 Hz, 1H), 4.27 (m, 1H), 3.86 (m, 1H), 3.07 (m, 2H),2.08 (m, 1H), 1.84 (m, 2H), 1.65 (m, 1H). 222

  (S)-4-(Pyrrolidin-2- ylmethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 5.87, 294, D (DMSO-D₆, 400 MHz):8.97 (s, 1H), 8.55 (s, 1H), 8.53 (d, J = 5.7 Hz, 1H), 7.03 (d, J = 5.8Hz, 1H), 4.23 (m, 1H), 4.15 (m, 1H), 3.70-3.55 (m, 1H), 2.90 (t, J = 6.5Hz, 2H), 1.98 (m, 1H), 1.85- 1.64 (m, 2H), 1.65-1.45 (m, 1H). 223

  4-(Azetidin-3-yloxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 5.27, 266, D (DMSO-D₆, 400 MHz): 8.98 (d, J= 0.8 Hz, 1H), 8.63 (s, 1H), 8.51 (d, J = 5.7 Hz, 1H), 6.75 (d, J = 5.7Hz, 1H), 5.46-5.30 (m, 1H), 4.01-3.86 (m, 2H), 3.86-3.72 (m, 2H). 224

  (R)-4-(Pyrrolidin-3-yloxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 5.56, 280, D (DMSO-D₆, 500 MHz): 8.95 (s, 1H), 8.60(s, 1H), 8.53 (d, J = 5.7 Hz, 1H), 7.01 (d, J = 5.8 Hz, 1H), 5.27 (s,1H), 3.13 (m, 2H), 3.10-3.05 (m, 1H), 2.85 (d, J = 8.0 Hz, 1H), 2.19 (m,1H), 2.01 (m, 1H). 225

  (S)-4-(Pyrrolidin-3- ylmethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 5.53, 280, D (DMSO-D₆, 500 MHz):8.95 (s, 1H), 8.60 (s, 1H), 8.53 (d, J = 5.7 Hz, 1H), 7.01 (d, J = 5.8Hz, 1H), 5.28 (m, 1H), 3.18 (m, 1H), 3.16-3.13 (m, 1H), 3.13-3.08 (m,1H), 2.88 (m, 1H), 2.21 (m, 1H), 2.07-1.99 (m, 1H). 226

  (R)-(Piperidin-3-yloxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 6.10, 294, D (DMSO-D₆, 500 MHz): 8.96 (d, J = 1.0Hz, 1H), 8.53 (d, J= 0.9 Hz, 1H), 8.51 (d, J = 5.8 Hz, 1H), 7.07 (d, J =5.9 Hz, 1H), 4.72 (m, 1H), 3.19 (m, 1H), 2.85 (m, 1H), 2.82- 2.76 (m,1H), 2.68-2.61 (m, 1H), 2.13 (s, 1H), 1.85 (m, 1H), 1.76 (m, 1H), 1.53(m, 1H). 227

  (R)-4-(Piperidin-3-ylmethoxy)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 6.26, 308, D (DMSO-D₆, 400 MHz): 8.97 (s,1H), 8.53 (d, J = 5.7 Hz, 1H), 8.41 (s, 1H), 7.02 (d, J = 5.8 Hz, 1H),4.23 (d, J = 6.4 Hz, 2H), δ 3.16 (m, 1H), 2.89 (m, 1H), 2.15 (m, 2H),1.91 (d, J = 9.6 Hz, 1H), 1.64 (m, 1H), 1.57-1.19 (m, 3H). 228

  (S)-4-(Piperidin-3-ylmethoxy)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 6.31, 308, D (DMSO-D₆, 400 MHz): 8.97 (s,1H), 8.53 (d, J = 5.7 Hz, 1H), 8.41 (s, 1H), 7.03 (d, J = 5.8 Hz, 1H),4.23 (d, J = 6.5 Hz, 2H), 3.17 (m, 1H), 2.89 (m, 1H), 2.15 (m, 2H), 1.90(m, 1H), 1.65 (m, 1H), 1.54- 1.20 (m, 3H). 229

  (R)-4-(Pyrrolidin-3- ylmethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 2.61, 294, E (DMSO-D₆, 400 MHz):8.98 (s, 1H), 8.55 (d, J = 5.7 Hz, 1H), 8.45 (s, 1H), 7.04 (d, J = 5.8Hz, 1H), 4.32 (m, 2H), 3.21 (m, 1H), 3.05 (m, 1H), 3.00-2.92 (m, 1H),2.92- 2.85 (m, 1H), 2.79 (m, 1H), 2.06 (m, 1H), 1.65 (m, 1H). 230

  (S)-4-(Pyrrolidin-3- ylmethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 2.66, 294, E (DMSO-D₆, 400 MHz):8.96 (d, J = 0.9 Hz, 1H), 8.53 (d, J = 5.7 Hz, 1H), 8.42 (s, 1H), 7.01(d, J = 5.7 Hz, 1H), 4.28 (m, 2H), 3.06 (m, 1H), 2.91 (m, 9.1, 1H),2.88- 2.64 (m, 3H), 1.98 (m, 7.9, 1H), 1.56 (m, 1H). 231

  4-(Piperidin-4-ylmethoxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C F T 2.67, 308, E (DMSO-D₆, 400 MHz): 8.97 (d, J = 0.8Hz, 1H), 8.54 (d, J = 5.7 Hz, 1H), 8.41 (s, 1H), 7.05 (d, J = 5.8 Hz,1H), 4.22 (d, J = 6.3 Hz, 2H), 3.05 (d, J = 11.8 Hz, 2H), 2.60 (m, 2H),2.10 (m, 1H), 1.83 (d, J = 10.9 Hz, 2H), 1.41-1.26 (m, 2H).

Example 2324-(Piperidin-4-ylamino)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1: tert-Butyl4-{6-cyano-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrol-4-ylamino}piperidine-1-carboxylate

A mixture of4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrilewith4-chloro-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(6.5:1, 85 mg, 0.24 mmol), tert-butyl 4-aminopiperidine-1-carboxylate(240 mg, 1.2 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.02mmol), and cesium carbonate (150 mg, 0.47 mmol) in 1,4-dioxane (2 mL)was sealed and heated at 110° C. for 2 h. The mixture was diluted withwater (20 mL) and ethyl acetate (50 mL). The organic layer wasseparated, dried over sodium sulfate, filtered, concentrated in vacuo,and purified flash chromatography (silica, 40 g, ISCO, 5-75% ethylacetate in heptane) to afford the title compound as a yellow solid (80mg, 60%).

Step 2:4-(Piperidin-4-ylamino)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

tert-Butyl4-{6-cyano-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrol-4-ylamino}piperidine-1-carboxylate(80 mg, 0.14 mmol) was dissolved in 1,4-dioxane (0.4 mL) and thentreated with 48% HBr_((aq))(0.5 mL) and heated at 75° C. for 15 minutes.The cooled reaction mixture was then basified to pH 6˜12 by dropwiseaddition of 6N sodium hydroxide and then immediately acidified to pH˜8-9 by dropwise addition of concentrated hydrochloric acid, producing acloudy precipitate. The solid was collected by centrifugation, dissolvedin dimethylsulfoxide (2 mL), and purified by preparative HPLC (5-85%methanol in water (0.1% formic acid) over 30 min, 35 mL/min) to affordthe title compound as a pale yellow solid (20 mg, 30% over two steps).¹H NMR (DMSO-D₆, 400 MHz): 9.08 (s, 1H), 8.83 (s, 1H), 8.20 (d, J=5.9Hz, 1H), 6.63 (d, J=6.0 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 3.74 (m, 1H),3.11 (m, 2H), 2.71 (m, 2H), 1.97 (m, 2H), 1.70 (m, 2H). LCMS (Method E):R_(T)=2.28 min, M+H⁺=293.

The compounds of the Examples in Table 11 were prepared via generalSuzuki procedures described above.

TABLE 11 Ex- Halide or Depro- LCMS R_(T), am- Coupling Mesylate tectionPurification M + H⁺, ple Structure/Name Method displacement MethodMethod(s) Method ¹H NMR (ppm) 233

  5-(3-Methylamino-propyl)-3-(1- meth

l-1H-pyrazol-4-yl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile LD/E — B 5.21, 346, A (DMSO-D₆, 400 MHz): 8.99 (d, J = 2.0 Hz, 1H), 8.92(s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.42 (s, 1H), 8.14 (d, J = 0.8 Hz,1H), 3.92 (s, 3H), 3.53 (t, J = 7.7 Hz, 2H), 3.10 (t, J = 7.8 Hz, 2H),2.54 (s, 3H), 2.16-2.06 (m, 2H). 234

  3-(1-Methyl-1H-pyrazol-4-yl)-5-(3- pyrrolidin-1-yl-propyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile L D — B 5.35, 385, A (CD₃OD, 400MHz): 8.84 (d, J = 2.1 Hz, 1H), 8.82-8.79 (m, 1H), 8.68 (d, J = 2.1 Hz,1H), 8.13-8.10 (m, 1H), 7.97 (d, J = 0.8 Hz, 1H), 3.96 (s, 3H), 3.53 (t,J = 7.8 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 2.57 (m, 4H), 2.09 (m, J =7.7 Hz, 2H), 1.78-1.71 (m, 4H). 235

  3-(1-Methyl-1H-pyrazol-4-yl)-5-(3-

orpholin-4-yl-propyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrileL D/E — B 5.50, 402, F (DMSO-D₆, 400 MHz): 12.83 (s, 1H), 8.96 (t, J =2.1 Hz, 1H), 8.88 (s, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.36 (s, 1H), 8.07(d, J = 0.8 Hz, 1H), 3.97- 3.90 (m, 3H), 3.52 (t, J = 7.4 Hz, 2H), 3.43(t, J = 4.4 Hz, 4H), 2.47 (t, J = 6.7 Hz, 2H), 2.27 (s, 4H), 2.03-1.93(m, 2H). 236

  3-(1-Methyl-1H-pyrazol-4-yl)-5- pip

ridin-4-ylmethyl-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrile M NAE B 6.08, 372, F (DMSO-D₆, 400 MHz): 12.99 (s, 1H), 12.66 (s, 1H), 9.01(d, J = 2.0 Hz, 1H), 8.96 (s, 1H), 8.70 (d, J = 2.1 Hz, 1H), 8.38 (s,1H), 8.12 (s, 1H), 3.97 (s, 3H), 3.50 (d, J = 7.2 Hz, 2H), 3.30 (d, J =12.5 Hz, 2H), 2.86 (t, J = 12.4 Hz, 2H), 2.20 (s, 1H), 1.90 (d, J = 13.9Hz, 2H), 1.71 (t, J = 13.0 Hz, 2H). 237

  5-(1-Ethyl-piperidin-4-ylmethyl)-3- (1-methyl-1H-pyrazol-4-yl)-9H-dipy

ido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile M F D C 5.96, 400, F (DMSO-D₆,400 MHz): 12.82 (s, 1H), 8.95 (d, J = 2.0 Hz, 1H), 8.87 (s, 1H), 8.62(d, J = 2.1 Hz, 1H), 8.32 (s, 1H), 8.04 (d, J = 0.8 Hz, 1H), 3.92 (s,3H), 3.40 (d, J = 7.0 Hz, 2H), 2.82 (d, J = 10.9 Hz, 2H), 2.23 (q, J =7.2 Hz, 2H), 1.82-1.61 (m, 5H), 1.55-1.41 (m, 2H), 0.93 (t, J = 7.1 Hz,3H). 238

  5-(1-Ethyl-piperidin-4-ylmethyl)-

- pyridin-4-yl-9H-dipyrido[2,3- b;4′,

′-d]pyrrole-6-carbonitrile M^(†) F D C 3.73, 397, F (DMSO-D₆, 400 MHz):13.03 (s, 1H), 9.14 (d, J = 2.1 Hz, 1H), 8.94 (s, 1H), 8.89 (d, J = 2.2Hz, 1H), 8.75-8.70 (m, 2), 7.94-7.89 (m, 2H), 3.46 (d, J = 7.1 Hz, 2H),2.87-2.79 (m, 2H), 2.24 (q, J = 7.2 Hz, 2H), 1.90-1.59 (m, 5H), 1.57-1.42 (m, 2H), 0.94 (t, J = 7.1 Hz, 3). ^(†)Deviation from method:9-Benzenesulfonyl5-bromo-3-pyridin-4-yl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrilewas used in place of9-benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile.

indicates data missing or illegible when filed

The compounds of the Examples in Table 12 were prepared via generalMitsunobu procedures followed by general Suzuki coupling describedabove.

TABLE 12 LCMS Depro- Puri- R_(T), Cou- tec- ficat- M + Ex- pling tionion H⁺, am- Amino Mitsunobu Meth- Meth- Meth- Meth- ple Structure/Namealcohol Method od od od(s) od ¹H NMR (ppm) 239

  3-(1-Methyl-1H-pyrazol-4-yl)-5- (piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylic acidtert- butyl ester A N F R³ 5.38, 374, A (DMSO-D₆, 400 MHz): 13.07 (s,1H), 9.00 (d, J = 2.1 Hz, 1H), 8.95 (s, 2H), 8.85 (s, 1H), 8.53 (d, J =2.1 Hz, 1H), 8.43 (s, 1H), 8.07 (d, J = 0.8 Hz, 1H), 5.01-4.94 (m, 1H),3.95 (s, 3H), 3.42 (d, J = 12.0 Hz, 2H), 3.12 (s, 2H), 2.34- 2.18 (m,4H). 240

  3-(1-Methyl-1H-pyrazol-4-yl)-5-((S)-piperidin-3-yloxy)-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile3-(S)- Hydroxy- piperidine carboxylic acid tert- butyl ester A N F R³5.37, 374, A (DMSO-D₆, 400 MHz): 13.14 (s, 1H), 9.42 (s, 2H), 9.00 (d, J= 2.0 Hz, 1H), 8.86 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H),8.12 (s, 1H), 5.01 (m, 1H), 3.95 (s, 3H), 3.72 (d, J = 11.5 Hz, 1H),3.51 (d, J = 10.1 Hz, 1H), 3.24-3.11 (m, 1H), 3.09 (d, J = 9.9 Hz, 1H),2.18 (s, 1H), 2.13-1.93 (m, 2H), 1.75 (d, J = 12.3 Hz, 1H). 241

  5-(1-Ethyl-piperidin-4-yloxy)-3-(1- methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile N-Ethyl 4- hydroxy-piperidine A N NA E² 5.44, 402, A (DMSO-D₆, 400 MHz): 12.92 (s, 1H),8.97 (d, J = 2.1 Hz, 1H), 8.78 (s, 1H), 8.57 (d, J = 2.2 Hz, 1H), 8.32(s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 4.81- 4.74 (m, 1H), 3.94 (s, 3H),2.91-2.83 (m, 2H), 2.35 (q, J = 7.2 Hz, 2H), 2.12 (d, J = 11.7 Hz, 4H),2.05-1.94 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H). 242

  3-(4-Morpholin-4-ylmethyl-phenyl)-5-(piperidin-4-yloxy)-9H-dipyrido[2, 3-b;4′,3′-d]pyrrole-6-carbonitrile4-Hydroxy- piperidine carboxylic acid tert- butyl ester A N A S 4.55,469, A (DMSO-D₆, 400 MHz): 13.23 (s, 1H), 11.52 (s, 1H), 9.07 (d, J =2.4 Hz, 2H), 8.88 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 7.98 (d, J = 7.8Hz, 2H), 7.82 (d, J = 7.8 Hz, 2H), 5.07- 4.99 (m, 1H), 4.42 (d, J = 5.3Hz, 2H), 3.97 (d, J = 12.7 Hz, 2H), 3.85 (t, J = 12.1 Hz, 2H), 3.43-3.35 (m, 2H), 3.28 (d, J = 12.6 Hz, 2H), 3.12 (s, 4H), 2.33-2.16 (m,4H). 243

  3-[4-(4,4-Difluoro-piperidin-1-ylmethyl)-phenyl]-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylicacid tert- butyl ester A N A S 4.93, 503, A (DMSO-D₆, 400 MHz): 13.21(s, 1H), 11.75 (s, 1H), 9.10-8.96 (m, 3H), 8.86-8.82 (m, 1H), 8.66 (d, J= 2.2 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 7.8 Hz, 2H), 5.06-4.97 (m, 1H), 4.45 (s, 2H), 3.52-3.30 (m, 4H), 3.21-3.15 (m, 2H), 3.10(d, J = 12.4 Hz, 2H), 2.36 (s, 3H), 2.33-2.17 (m, 5H). 244

  5-(Piperidin-4-yloxy)-3-[4-(4-trifluoromethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylicacid tert- butyl ester A N A S 5.14, 535, A (DMSO-D₆, 400 MHz): 13.25(s, 1H), 11.25 (s, 1H), 9.10 (d, J = 2.4 Hz, 3H), 8.89 (s, 1H), 8.69 (d,J = 2.2 Hz, 1H), 8.00 (d, J = 7.9 Hz, 2H), 7.83 (d, J = 7.9 Hz, 2H),5.09- 5.02 (m, 1H), 4.39 (d, J = 5.0 Hz, 2H), 3.50 (d, J = 12.2 Hz, 2H),3.46- 3.36 (m, 2H), 3.19-2.96 (m, 4H), 2.69 (s, 1H), 2.35-2.19 (m, 4H),2.10- 1.91 (m, 4H). 245

  3-(4-Hydroxymethyl-phenyl)-5- (piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylic acidtert- butyl ester A N A S 5.62, 400, A (DMSO-D₆, 400 MHz): 13.17 (s, 1H)9.07 (d, J = 10.0 Hz, 1H), 9.02 (t, J = 2.2 Hz, 1H), 8.95-8.84 (m, 1H),8.91-8.82 (m, 1H), 8.61 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H),7.50 (d, J = 8.0 Hz, 2H), 5.06-4.98 (m, 1H), 4.59 (s, 2H), 3.39 (m, 2H),3.10 (d, J = 11.3 Hz, 2H) 2.31-2.12 (m, 4H). 246

  5-(Piperidin-4-yloxy)-3-pyridin-4-yl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile 4-Hydroxy- piperidinecarboxylic acid tert- butyl ester A N A R⁷ 4.16, 371, A (DMSO-D₆, 400MHz): 13.52 (s, 1H), 9.33 (d, J = 2.2 Hz, 1H), 9.30 (s, 1H); 9.19 (s,1H), 8.96 (d, J = 6.2 Hz, 2H), 8.94- 8.90 (m, 2H), 8.53 (d, J = 6.0 Hz,2H), 5.12-5.03 (m, 1H), 3.39 (s, 2H), 3.11 (t, J = 8.8 Hz, 2H) 2.34-2.28(m, 4H). 247

  5-(Piperidin-4-yloxy)-3-pyridin-3-yl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile 4-Hydroxy- piperidinecarboxylic acid tert- butyl ester A N A R⁷ 4.58, 371, A (DMSO-D₆, 400MHz): 13.36 (s, 1H), 9.36 (s, 1H), 9.16 (d, J = 2.3 Hz, 2H), 8.90 (s,1H), 8.84- 8.77 (m, 3H), 7.95 (dd, J = 8.1, 5.3 Hz, 1H), 5.09- 5.01 (m,1H), 3.38 (d, J = 11.8 Hz, 2H), 3.10 (d, J = 10.4 Hz, 2H), 2.31- 2.22(m, 4H). 248

  3-(4-Methoxy-pyridin-3-yl)-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile 4-Hydroxy-piperidine carboxylic acid tert- butyl ester A N A R⁷ 4.11, 401, A(DMSO-D₆, 400 MHz): 13.35 (s, 1H), 9.19 (s, 2H), 9.04 (s, 1H), 8.95-8.93 (m, 1H), 8.91-8.82 (m, 2H), 8.73 (d, J = 2.1 Hz, 1H), 7.78 (d, J =6.8 Hz, 1 H), 5.04-4.97 (m, 1H), 4.16 (s, 3H), 3.38 (m, 2H), 3.09 (d, J= 10.8 Hz, 2H), 2.32- 2.16 (m, 4H). 249

  3-(5-Methoxy-pyridin-3-yl)-5- (piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylic acidtert- butyl ester A N A R⁷ 5.23, 401, A (DMSO-D₆, 400 MHz): 13.35 (s,1H), 9.16 (d, J = 2.2 Hz, 2H), 8.99 (s, 1H), 8.90-8.86 (m, 2H), 8.76 (d,J = 2.2 Hz, 1H), 8.53 (d, J = 2.6 Hz, 1H), 8.22 (s, 1H), 5.10-5.02 (m,1H), 4.04 (s, 3H), 3.38 (m, 2H), 3.11 (d, J = 11.0 Hz, 2H), 2.34- 2.17(m, 4H). 250

  3-(2-Methoxy-pyridin-3-yl)- 5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile 4-Hydroxy- piperidinecarboxylic acid tert- butyl ester A N B C² 5.78, 401, A (DMSO-D₆, 400MHz): 8.86 (t, J = 2.2 Hz, 1H), 8.81 (s, 1H), 8.78 (d, J = 2.2 Hz, 1H),8.26 (dd, J = 5.0, 1.8 Hz, 1H), 7.99- 7.94 (m, 1H), 7.20 (dd, J = 7.3,5.0 Hz, 1H), 4.83- 4.75 (m, 1H), 3.99-3.92 (m, 3H), 3.08-3.01 (m, 2H),2.59-2.52 (m, 2H), 2.06 (d, J = 11.9 Hz, 2H), 1.85-1.74 (m, 2H). 251

  3-(6-Methoxy-pyridin-3-yl)-5- (piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylicacid tert- butyl ester A N B C² 7.36, 401, F (DMSO-D₆, 400 MHz): 8.99(d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.60 (dd, J= 2.6, 0.8 Hz, 1H), 8.15 (dd, J = 8.6, 2.6 Hz, 1H), 7.01 (dd, J = 8.6,0.7 Hz, 1H), 4.86-4.77 (m, 1H), 3.94 (s, 3H), 3.10-3.01 (m, 2H),2.62-2.52 (m, 2H), 2.07 (d, J = 11.9 Hz, 2H), 1.87-1.76 (m, 2H). 252

  3-(3-Methoxy-pyridin-4-yl)-5-(piperidin- 4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylicacid tert- butyl ester A N A R¹ 5.10, 401, F (DMSO-D₆, 400 MHz): 13.38(s, 1H), 9.14 (s, 2H), 9.02 (d, J = 2.1 Hz, 1H), 8.89 (s, 1H), 8.81 (d,J = 2.1 Hz, 1H), 8.75 (s, 1H), 8.59 (d, J = 5.4 Hz, 1H), 8.10 (d, J =5.4 Hz, 1H) 5.03-4.96 (m, 1H), 4.07 (s, 3H), 3.37 (m, 2H), 3.08 (d, J =10.6 Hz, 2H), 2.32- 2.14 (m, 4H). 253

  3-(2-Methoxy-pyridin-4-yl)-5- (piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylicacid tert- butyl ester A N B E⁵ 7.33, 401, F (DMSO-D₆, 400 MHz): 9.09(d, J = 2.2 Hz, 1H), 8.81 (s, 1H), 8.72 (d, J = 2.3 Hz, 1H), 8.31 (d, J= 5.4 Hz, 1H), 7.44 (dd, J = 5.4, 1.6 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H),4.87- 4.78 (m, 1H), 3.94 (s, 3H), 3.12-3.01 (m, 2H), 2.62-2.52 (m, 2H),2.08 (d, J = 11.9 Hz, 2H), 1.88-1.77 (m, 2H). 254

  5-(1-Ethyl-piperidin-4-yloxy)-3-(4- hydroxymethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine AN² D B⁸ 6.89, 428, F (CDCl₃ and CD₃OD, 400 MHz): 8.90 (d, J = 2.2 Hz, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.75 (s, 1H), 7.73-7.69 (m, 2H), 7.57-7.52(m, 2H), 5.04- 4.94 (m, 1H), 4.72 (s, 2H), 3.04-2.95 (m, 2H), 2.49 (q, J= 7.2 Hz, 2H), 2.38-2.19 (m, 4H), 2.18- 2.07 (m, 2H), 1.12 (t, J = 7.2Hz, 3H). 255

  5-(1-Ethyl-piperidin-4-yloxy)-3-p- tolyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² D B⁵ 8.41,412, F (CDCl₃ and CD₃OD, 400 MHz): 8.85 (d, J = 2.2 Hz, 1H), 8.76 (d, J= 2.1 Hz, 1H), 8.73 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 7.9Hz, 2H), 5.06-4.96 (m, 1H), 3.04-2.92 (m, 2H), 2.54- 2.43 (m, 5H),2.38-2.20 (m, 4H), 2.18-2.07 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). 256

  5-(1-Ethyl-piperidin-4-yloxy)-3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² D B⁵ 7.87, 456, F(CDCl₃ and CD₃OD, 400 MHz): 8.90 (d, J = 2.2 Hz, 1 H), 8.79 (d, J = 2.2Hz, 1H), 8.76 (s, 1H), 7.68-7.67 (s, 4H), 5.06-4.95 (m, 1H), 3.05- 2.96(m, 2H), 2.50 (q, J = 7.2 Hz, 2H), 2.38-2.20 (m, 4H), 2.19-2.08 (m, 2H),1.63 (s, 6H), 1.13 (t, J = 7.2 Hz, 3H). 257

  5-(1-Ethyl-piperidin-4-yloxy)-3-(4-hydroxymethyl-3-methoxy-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² D B⁵ 7.29, 458, F(CDCl₃ and CD₃OD, 400 MHz): 8.91 (d, J = 2.2 Hz, 1 H), 8.78 (d, J = 2.2Hz, 1H), 8.76 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.29 (dd, J = 7.7, 1.7Hz, 1H), 7.22 (d, J = 1.6 Hz, 1H), 5.05-4.95 (m, 1H), 4.74 (s, 2H), 3.98(s, 3H), 3.03-2.94 (m, 2H), 2.49 (q, J = 7.2 Hz, 2H), 2.40-2.29 (m, 2H),2.28-2.20 (m, 2H), 2.19-2.08 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H). 258

  3-(4-tert-Butyl-phenyl)-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrileN-Ethyl 4- hydroxy- piperidine A N² D B⁵ 9.86, 454, F (DMSO-D₆, 400MHz): 13.03 (s, 1H), 9.00 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.68 (d, J= 2.3 z, 1H), 7.75-7.70 (m, 2H), 7.61-7.55 (m, 2H), 4.88 (m, 1H), 2.92-2.80 (m, 2H), 2.40-2.29 (m, 2H), 2.21-2.04 (m, 4H), 2.02-1.89 (m, 2H),1.35 (s, 9H), 0.99 (t, J = 7.1 Hz, 3H). 259

  3-(4-tert-Butyl-3-methoxy-phenyl)-5- (1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile N-Ethyl 4- hydroxy-piperidine A N² D B⁵ 10.17, 484, F (DMSO-D₆, 400 MHz): 13.05 (s, 1H),9.05 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 7.39(d, J = 8.0 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 7.29 (dd, J = 8.0, 1.8Hz, 1H), 4.87-4.77 (m, 1H), 3.96 (s, 3H), 2.87-2.79 (m, 2H), 2.33 (q, J= 7.1 Hz, 2H), 2.21- 2.05 (m, 4H), 2.03-1.90 (m, 2H), 1.39 (s, 9H), 0.98(t, J = 7.2 Hz, 3 H). 260

  5-(1-Ethyl-piperidin-4-yloxy)-3-(4- hydroxymethyl-3-trifluoromethoxy-phenyl)-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile N-Ethyl 4-hydroxy- piperidine A N² D B¹ 8.49, 512, F (DMSO-D₆, 400 MHz): 13.10 (s,1H), 9.06 (d, J = 2.2 Hz, 1H), 8.82 (s, 1H), 8.69 (d, J = 2.3 Hz, 1H),7.88 (dd, J = 8.1, 1.7 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H),5.46 (t, J = 5.7 Hz, 1H), 4.90-4.81 (m, 1H), 4.65 (d, J = 5.6 Hz, 2H),2.86-2.76 (m, 2,H), 2.34 (q, J = 7.1 Hz, 2H), 2.23- 2.04 (m, 4H),2.03-1.90 (m, 2H), 0.99 (t, J = 7.1 Hz, 3H). 261

  5-(1-Ethyl-piperidin-4-yloxy)-3-pyridin-4-yl-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile N-Ethyl4- hydroxy- piperidine A N NA B/ C² 4.42, 399, F (DMSO-D₆, 400 MHz):13.07 (s, 1H), 9.14 (d, J = 2.2 Hz, 1H), 8.84-8.79 (m, 2H), 8.72 (d, J =5.3 Hz, 2H), 7.87 (dd, J = 4.8, 1.6 Hz, 2H), 4.89- 4.80 (m, 1H),2.92-2.81 (m, 2H), 2.36 (q, J = 7.2 Hz, 2H), 2.23-2.06 (m, 4H),2.04-1.93 (m, 2H), 1.00 (t, J = 7.1 Hz, 3H). 262

  5-(1-Ethyl-piperidin-4-yloxy)-3-(6- methoxy-pyridin-3-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A NNA B² 7.45, 429, F (DMSO-D₆, 400 MHz): 13.02 (s, 1H), 8.99 (d, J = 2.2Hz, 1H), 8.80 (s, 1H), 8.66 (d, J = 2.3 Hz, 1H), 8.60 (d, J = 2.6 Hz,1H), 8.15 (dd, J = 8.6, 2.6 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 4.86-4.75(m, 1H), 3.94 (s, 3H), 2.92-2.79 (m, 2H), 2.35 (q, J = 7.2 Hz, 2H),2.21- 2.04 (m, 4H), 2.03-1.90 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 263

  5-(1-Ethyl-piperidin-4-yloxy)-3-pyridin-3-yl-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile N-Ethyl4- hydroxy- piperidine A N NA B^(2/6) 5.53, 399, F (DMSO-D₆, 400 MHz):13.21 (s, 1H), 9.09 (d, J = 2.2 Hz, 1H), 9.06 (d, J = 2.4 Hz, 1H), 8.86(s, 1H), 8.73 (d, J = 2.2 Hz, 1H) 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.29(d, J = 8.0 Hz, 1H), 7.61-7.56 (m, 1H), 4.95 (s, 1 H), 3.22-2.63 (m,4H), 2.38- 2.03 (m, 4H), 1.27-1.06 (m, 3H). 264

  5-(1-Ethyl-piperidin-4-yloxy)-3-[4-(4-trifluoromethyl-piperidin-1-ylmethyl)- phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine AN² NA B⁸ 5.68, 563, F (CDCl₃ and CD₃OD, 400 MHz): 8.85 (s, 1H), 8.78 (s,1H), 8.73 (s, 1H), 7.63 (d, J = 7.7 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H),5.02 (s, 1H), 3.61 (s, 2H), 3.09-3.01 (m, 2H), 3.01-2.93 (m, 2H),2.53-2.42 (m, 2H), 2.33- 2.19 (m, 4H), 2.16-1.98 (m, 5H), 1.92-1.83 (m,2H), 1.76-1.62 (m, 2H), 1.17-1.06 (m, 3H). 265

  3-[4-(4,4-Difluoro-piperidin-1- ylmethyl)-phenyl]-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrileN-Ethyl 4- hydroxy- piperidine A N² NA B 5.46, 531, F (CDCl₃, 400 MHz):10.67 (s, 1H), 8.92 (d, J = 2.1 Hz, 1 H), 8.81 (s, 1H) 8.78 (s, 1,H),7.62 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 5.11- 5.01 (m, 1H),3.66 (s, 2H), 3.09-2.94 (m, 2H), 2.68-2.59 (m, 4H), 2.56- 2.42 (m, 2H),2.37-2.18 (m, 4H), 2.17-1.98 (s, 6H), 1.18-1.05 (m, 3H). 266

  3-(4-Chloro-phenyl)-5-(1-ethyl- piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² NAB 8.58, 432, F (CDCl₃ and CD₃OD, 400 MHz): 8.82 (d, J = 2.2 Hz, 1H),8.76 (s, 1H), 8.74 (s, 1H), 7.65- 7.58 (m, 2H), 7.55-7.50 (m, 2H),5.08-4.97 (m, 1H), 3.02-2.91 (m, 2H), 2.52-2.42 (m, 2H), 2.34- 2.19 (m,4H), 2.17-2.03 (m, 2H), 1.16-1.07 (m, 3H). 267

  5-(1-Ethyl-piperidin-4-yloxy)-3-(4- fluoro-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² NAB³ 8.04, 416, F (CDCl₃ and DMSO-D₆, 400 MHz): 12.39 (s, 1H), 8.84 (d, J= 2.2 Hz, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 7.66-7.58 (m, 2H), 7.27-7.20(m, 2H), 4.96 (s, 1H), 3.06-2.91 (m, 2H), 2.53-2.39 (m, 2H), 2.30-1.99(m, 6H), 1.16- 1.04 (m, 3H). 268

  5-(1-Ethyl-piperidin-4-yloxy)-3-(3- fluorophenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² NAB 8.23, 416, F (CDCl₃, 400 MHz): 10.20 (s, 1H), 8.89 (d, J = 2.2 Hz,1H), 8.80 (s, 1H), 8.78 (s, 1H), 7.56- 7.48 (m, 1H), 7.46-7.42 (m, 1H),7.36 (dt, J = 9.8, 2.0 Hz, 1H), 7.19- 7.13 (m, 1H), 5.14-5.04 (m, 1H),3.03-2.90 (m, 2H), 2.53-2.41 (m, 2H), 2.33-2.19 (m, 4H), 2.16- 2.03 (m,2H), 1.11 (t, J = 7.2 Hz, 3H). 269

  3-(4-Cyano-phenyl)-5-(1-ethyl- piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² NAB³ 7.51, 423, F (CDCl₃ and DMSO-D₆, 400 MHz): 12.54 (s, 1H) 8.89 (d, J =2.2 Hz, 1H), 8.79 (s, 1H), 8.77-8.68 (m, 1H), 7.87-7.74 (m, 4H),5.05-4.92 (m, 1H), 3.10-2.87 (m, 2H), 2.57- 2.37 (m, 2H), 2.35-1.97 (m,6H), 1.22-1.02 (m, 3H). 270

  5-(1-Ethyl-piperidin-4-yloxy)-3- phenyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² NA B³ 7.92,398, F (CDCl₃ and DMSO-D₆, 400 MHz): 12.37 (s, 1H), 8.89 (d, J = 2.2 Hz,1H), 8.78 (s, 1H), 8.75-8.65 (m, 1H), 7.69-7.62 (m, 2H), 7.57-7.50 (m,2H), 7.47-7.40 (m, 1H), 4.97 (s, 1H), 3.10-2.87 (m, 2H), 2.55-2.37 (m,2H), 2.34-2.05 (m, 6H), 1.21- 1.03 (m, 3H). 271

  3-(2-Chloro-phenyl)-5-(1-ethyl- piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² NAB³ 8.08, 432, F (CDCl₃, 400 MHz): 10.64 (s, 1H), 8.82 (s, 1H), 8.78 (d,J = 2.1 Hz, 1H), 8.73 (s, 1H), 7.61- 7.56 (m, 1H), 7.48-7.39 (m, 3H),5.08-4.96 (m, 1H), 3.06-2.88 (m, 2H), 2.53-2.38 (m, 2H), 2.32- 2.00 (m,6H), 1.16-1.01 (m, 3H). 272

  3-(3-Chloro-phenyl)-5-(1-ethyl- piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N² NAB³ 8.66, 432, F (CDCl₃, 400 MHz): 10.34 (s, 1H), 8.88 (d, J = 2.2 Hz,1H), 8.82 (s, 1H), 8.77 (s, 1H), 7.64 (s, 1H), 7.56-7.41 (m, 3H),5.17-5.05 (m, 1H), 3.06-2.88 (m, 2H), 2.56- 2.40 (m, 2H), 2.38-2.20 (m,4H), 2.19-2.05 (m, 2H), 1.17-1.05 (m, 3H). 273

  3-Bromo-5-(1-ethyl-piperidin-4- yloxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A N A DB 6.43, 400/ 402, F (400 MHz, CD₃OD): 8.71 (s, 1H), 8.70 (d, J = 2.2 Hz,1H), 8.66 (d, J = 2.3 Hz, 1H), 5.00-4.91 (m, 1H), 3.03-2.95 (m, 2H),2.51 (q, J = 7.3 Hz, 2H), 2.36-2.25 (m, 2H), 2.24-2.15 (m, 2H), 2.12-2.00 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H). 274

  3-(1-Isopropyl-1H-pyrazol-4-yl)-5- (piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylicacid tert- butyl ester A Stille C B ¹C 7.27, 402, F (DMSO-D₆, 400 MHz):13.03 (s, 1H), 9.01 (d, J = 2.1 Hz, 1H), 8.83 (s, 1H), 8.55 (br s, 1H),8.53 (d, J = 2.2 Hz, 1H), 8.41 (s, 1H), 8.05 (s, 1H), 5.02-4.93 (m, 1H),4.63-4.51 (m, 1H), 3.47- 3.38 (m, 2H), 3.18-3.06 (m, 2H), 2.35-2.24 (m,2H), 2.22-2.10 (m, 2H), 1.49 (d, J = 6.7 Hz, 6H). 275

  3-(3-Methoxy-4-methyl-phenyl)-5- (piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 4-Hydroxy- piperidine carboxylicacid tert- butyl ester A N B C² 8.66, 414, F (CD₃OD and CDCl₃, 400 MHz):8.84 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 8.7 Hz, 2H), 7.34-7.27 (m, 1H),7.14 (d, J = 7.7 Hz, 1H), 7.08 (s, 1H), 5.06-4.96 (m, 1H), 3.95 (s, 3H),3.27-3.17 (m, 2H), 2.79-2.68 (m, 2H), 2.31 (s, 3H), 2.29- 2.19 (m, 2H),2.01-1.89 (m, 2H). 276

  5-(1-Ethyl-piperidin-4-yloxy)-3-(3-methoxy-4-methyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Ethyl 4- hydroxy- piperidine A NNA B 8.79, 442, F (CDCl₃, 400 MHz): 10.81 (s, 1H), 8.91 (d, J = 2.1 Hz,1H), 8.81 (s, 1H), 8.75 (s, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.14 (dd, J =7.6, 1.7 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 5.11-5.02 (m, 1H), 3.96 (s,3H), 3.09-2.88 (m, 2H), 2.57-2.40 (m, 3H), 2.38-2.05 (m, 8H), 1.20- 1.02(m, 3H). 277

  3-(4-Hydroxymethyl-3-methoxy-phenyl)-5-(piperidin-4-yloxy)-9H-dipyrido [2,3-b;4′,3′-d]pyrrole-6-carbonitrile4-Hydroxy- piperidine carboxylic acid tert- butyl ester A N B C 5.86,430, A (DMSO-D₆, 400 MHz): 9.05 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.66(d, J = 2.2 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.36 (dd, J = 7.8, 1.6Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 4.88- 4.78 (m, 1H), 4.57 (s, 2H),3.92 (s, 3H), 3.10- 3.01 (m, 2H), 2.60-2.51 (m, 2H), 2.13-2.04 (m, 2H),1.88-1.75 (m, 2H). 278

  5-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)- 3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile 3- Quinuclininol A N NAC⁸ 6.25, 400, F (DMSO-D₆, 300 MHz): 12.90 (s, 1H); 8.95 (d, J = 2.1 Hz,1H), 8.75 (s, 1H), 8.50 (d, J = 2.2 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H),5.06-4.98 (m, 1H), 3.93 (s, 3H), 3.45- 3.26 (m, 1H), 3.17-2.95 (m, 2H),2.92-2.78 (m, 1H), 2.77-2.56 (m, 2H), 2.29-2.10 (m, 2H), 1.77- 1.63 (m,1H), 1.56-1.42 (m, 2H). 279

  5-(1-Ethyl-piperidin-4-yloxy)-3-(4- morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile N-Ethyl 4- hydroxy-piperidine A N NA B⁵ 4.72, 497, F (CDCl₃, 400 MHz): 10.01 (s, 1H), 8.91(s, 1H), 8.84-8.71 (m, 2H), 7.65-7.56 (m, 2H), 7.55- 7.49 (m, 2H),5.12-5.01 (m, 1H), 3.77 (t, J = 4.5 Hz, 4H), 3.61 (s, 2H), 2.99 (s, 2H),2.57- 2.41 (m, 5H), 2.37-2.00 (m, 4H), 1.73-1.50 (br s, 4H), 1.20-1.04(br s, 2H). 280

  3-(1-Methyl-1H-pyrazol-4-yl)-5-(1-propyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N-Propyl 4- hydroxy- piperidine AN NA Q 6.75, 416, F (DMSO-D₆, 300 MHz): 12.91 (br s, 1H), 8.96 (d, J =2.1 Hz, 1H), 8.76 (d, J = 0.5 Hz, 1H), 8.56 (d, J = 2.2 Hz, 1H), 8.30(s, 1 H), 7.99 (s, 1H), 4.83- 4.71 (m, 1H), 3.92 (s, 3H), 2.89-2.77 (m,2H), 2.24 (t, J = 7.4 Hz, 2H), 2.18-1.88 (m, 6H), 1.51- 1.35 (m, 2H),0.84 (t, J = 7.4 Hz, 3H). 281

  5-((S)-1-Ethyl-pyrrolidin-3-yloxy)- 3-pyridin-4-yl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (R)-1-Ethyl- pyrrolidin- 3-ol A N NA B3.40, 385, F (DMSO-D₆, 400 MHz): 13.11 (s, 1H), 9.15 (d, J = 2.3 Hz,1H), 9.06 (d, J = 2.3 Hz, 1H), 8.82 (s, 1H), 8.71 (dd, J = 4.7, 1.6 Hz,2H), 7.85 (dd, J = 4.6, 1.7 Hz, 2H), 5.49- 5.44 (m, 1H), 3.20-3.13 (m,1H), 3.10-3.03 (m, 1H), 2.55-2.22 (m, 5H), 2.21-2.11 (m, 1H), 0.94 (t, J= 7.2 Hz, 3H). 282

  trans-3-[4-(4,4-Difluoro-piperidin-1- ylmethyl)-phenyl]-5-(-1-ethyl-3-fluoro-piperidin-4-yloxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile cis-1-Ethyl- 3-fluoro- piperidin- 4-ol A N NA B⁴ 4.73,340, F (CDCl₃ 400 MHz): 10.70 (s, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.85(s, 1H), 8.83 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 7.5 Hz,2H), 5.14- 4.79 (m, 2H), 3.74-3.60 (m, 2H), 3.38-3.23 (m, 1H), 3.07-2.93(m, 1H), 2.74-2.41 (m, 6H), 2.26- 1.96 (m, 6H), 1.69-1.48 (m, 2H),1.18-1.03 (m, 3H). 283

  3-Pyridin-4-yl-5-[1-(2,2,2-trifluoro- ethyl)-piperidin-4-yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile 1-(2,2,2- Tri-fluoroethyl) piperidin- 4-ol A N NA B, Q¹ 9.41, 453, F (CDCl₃ and CD₃OD,300 MHz): 9.00 (d, J = 2.2 Hz, 1H), 8.87 (d, J = 2.3 Hz, 1H), 8.78 (s,1H), 8.74-8.67 (m, 2H), 7.80-7.74 (m, 2H), 5.09- 4.96 (m, 1H), 3.18-3.02(m, 4H), 2.72-2.57 (m, 2H), 2.32-2.07 (m, 4H). 284

  5-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-3-pyridin-4-yl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 8-Methyl-8- azabicyclo [3.2.1]octan-3-ol A N NA E¹ 4.40, 411, F (DMSO-D₆, 300 MHz): 13.03 (br s, 1H),9.14 (d, J = 2.2 Hz, 1H), 8.81- 8.78 (m, 2H), 8.75-8.71 (m, 2H),7.88-7.83 (m, 2H), 5.15-4.99 (m, 1H), 3.25-3.17 (m, 2H), 2.25 (s, 3H),2.06 (dd, J = 8.4, 2.9 Hz, 4H), 1.94- 1.86 (m, 2H), 1.54-1.43 (m, 2H).285

  5-(1-Isopropyl-piperidin-4-yloxy)-3- pyridin-4-yl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 1-Isopropyl- piperidin- 4-ol A NNA E 4.93, 413, F (CDCl₃ and CD₃OD, 300 MHz): 8.99 (d, J = 2.3 Hz, 1H),8.91 (d, J = 2.3 Hz, 1H), 8.78 (s, 1H), 8.73-8.66 (m, 2H), 7.81-7.75 (m,2H), 5.09- 4.93 (m, 1H), 3.05-2.90 (m, 2H), 2.88-2.71 (m, 1H), 2.53-2.35(m, 2H), 2.33-2.00 (m, 4H), 1.09 (d, J = 6.5 Hz, 6H). 286

  5-(1-(2-Methoxy-ethyl)-piperidin-4- yloxy]-3-pyridin-4-yl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile 1-(2- Methoxy- ethyl)- 4-piperidinol A N NA E² 4.76, 429, F (CDCl₃ and CD₃OD, 300 MHz): 9.01 (d,J = 2.2 Hz, 1 H), 8.91 (d, J = 2.3 Hz, 1H), 8.78 (s, 1H), 8.73-8.66 (m,2H), 7.84-7.78 (m, 2H), 5.08- 4.95 (m, 1H), 3.56 (t, J = 5.5 Hz, 2H),3.10-2.97 (m, 2H), 2.65 (t, J = 5.5 Hz, 2H), 2.45-2.32 (m, 2H),2.31-2.07 (m, 4H).

The compounds of the Examples in Table 13 were prepared via the generalalkylation procedure followed by the general bromide displacementprocedures described above.

TABLE 13 Ex- Bromide LCMS am- Akylation Displacement Purification R_(T),M + H⁺, ple Structure/Name Method Method Method(s) Method ¹H NMR (ppm)287

  5-(3-Methylamino-propoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A E Q 5.29, 362, A (CD₃OD, 400 MHz):8.84 (d, J = 2.2 Hz, 1H), 8.73- 8.69 (m, 1H), 8.62 (d, J = 2.2 Hz, 1H),8.06 (s, 1H), 7.92 (s, 1H), 4.70 (t, J = 6.1 Hz, 2H), 4.05-3.96 (m, 3H),3.00 (t, J = 7.2 Hz, 2H), 2.51 (s, 3H) 2.32-2.22 (m, 2H). 288

  5-(3-Dimethylamino-propoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3- b;4′,3′-d]pyrrole-6-carbonitrile A E Q4.96, 362, A (CD₃OD, 400 MHz): 8.83 (s, 2H), 8.71 (s, 1H), 8.08 (s, 1H),7.94-7.92 (m, 1H), 4.70 (t, J = 5.4 Hz, 2H), 4.02-3.97 (m, 3H), 3.00 (t,J = 5.4 Hz, 2H), 2.44 (s, 6H). 289

  5-(3-Dimethylamino-propoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A E Q 5.20, 388, A (DMSO-D₆, 400 MHz,DMSO-d₆): 12.89 (s, 1H), 8.95 (d, J = 2.2 Hz, 1H), 8.80 (d, J = 2.2 Hz,1H), 8.79-8.75 (m, 1H), 8.28 (s, 1H), 7.99 (d, J = 0.8 Hz, 1H), 4.66 (t,J = 5.4 Hz, 2H), 3.93 (s, 3H), 3.00 (t, J = 5.3 Hz, 2H), 2.54 (s, 4H),1.66-1.50 (m, 4H).

The compounds of the Examples in Table 14 were prepared via the generalbromide displacement procedures described above.

TABLE 14 Ex- Bromide LCMS am- Displacement Purification R_(T), M + H⁺,ple Structure/Name Method Method(s) Method ¹H NMR (ppm) 290

  5-(1-Ethyl-piperidin-4-ylamino)-3- (1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile B C, Q, B 5.85, 401, F(CDCl₃ and MeOD, 400 MHz): 8.73 (d, J = 2.0 Hz, 1 H); 8.62 (d, J = 2.0Hz, 1 H); 8.40 (s, 1 H); 8.03 (s, 1 H); 7.95 (d, J = 0.8 Hz, 1 H);4.17-4.07 (m, 1 H); 4.02 (s, 3 H); 3.11-3.01 (m, 2 H); 2.51 (q, J = 7.2Hz, 2 H); 2.29-2.12 (m, 4 H); 1.92- 1.78 (m, 2 H); 1.16 (t, J = 7.2 Hz,3 H). 291

  3-(1-Methyl-1H-pyrazol-4-yl)-5-(2- pyrrolidin-1-yl-ethylamino)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile B C, B¹ 5.84, 387, F(CDCl₃ and MeOD, 400 MHz): 8.75 (d, J = 2.0 Hz, 1 H); 8.72 (d, J = 2.0Hz, 1 H); 8.37 (s, 1 H); 8.03 (s, 1 H); 7.91 (s, 1 H); 4.02-3.97 (m, 5H); 2.98 (t, J = 6.1 Hz, 2 H); 2.76-2.68 (m, 4 H); 1.86-1.77 (m, 4 H).292

  5-(3-Dimethylamino-propylamino)-3- (1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile B C, B² 6.09, 375, F(CDCl₃ and MeOD, 400 MHz): 8.87 (d, J = 2.0 Hz, 1 H); 8.73 (d, J = 2.0Hz, 1 H); 8.38 (s, 1 H); 8.07 (s, 1 H); 7.96 (d, J = 0.8 Hz, 1 H); 4.02(s, 3 H); 3.99 (t, J = 6.9 Hz, 2 H); 2.72 (t, J = 7.1 Hz, 2 H); 2.44 (s,6 H); 2.16-2.06 (m, 2 H). 293

  5-(4-Ethyl-piperazin-1-yl)-3-(1- methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile A Q¹ 5.15, 387, F (CDCl₃and MeOD, 400 MHz): 8.82 (d, J = 2.1 Hz, 1 H); 8.74- 8.71 (m, 2 H); 8.05(s, 1 H); 7.90 (d, J = 0.8 Hz, 1 H); 4.02 (s, 3 H); 3.71-3.64 (m, 4 H);2.94-2.84 (m, 4 H); 2.67 (q, J = 7.2 Hz, 2 H); 1.25 (t, J = 7.2 Hz, 3H). 294

  3-Bromo-5-(4-ethyl-piperazin-1-yl)- 9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C B¹ 4.62, 385, F (CDCl₃ and MeOD, 400 MHz): 8.78 (d, J =2.2 Hz, 1 H); 8.75 (s, 1 H); 8.70 (d, J = 2.2 Hz, 1 H); 3.68-3.61 (m, 4H); 2.90- 2.81 (m, 4 H); 2.65 (q, J = 7.25 Hz, 2 H); 1.24 (t, J = 7.2Hz, 3 H). 295

  3-Bromo-5-(1-ethyl-piperidin-4- ylamino)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile C C, Q 2.84, 399, G (CDCl₃ and MeOD, 400 MHz):8.70 (d, J = 2.1 Hz, 1 H); 8.62 (d, J = 2.1 Hz, 1 H); 8.43 (s, 1 H);4.22-4.08 (m, 1 H); 3.12- 3.01 (m, 2 H); 2.52 (q, J = 7.2 Hz, 2 H);2.31-2.14 (m, 4 H); 1.93-1.74 (m, 2 H); 1.16 (t, J = 7.2 Hz, 3 H). 296

  3-Bromo-5-(4-diethylamino- piperidin-1-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D C, B 2.57, 427, G (CDCl₃ and MeOD,400 MHz): 8.73-8.71 (m, 2 H); 8.69 (d, J = 2.2 Hz, 1 H); 3.68-3.54 (m,4H); 2.96-2.86 (m, 1 H); 2.80 (q, J = 7.2 Hz, 4 H); 2.19-2.11 (m, 2 H);1.99-1.86 (m, 2 H); 1.17 (t, J = 7.2 Hz, 6 H). 297

  3-Bromo-5-[4-(2-methoxy-ethyl)- piperazin-1-yl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D C, B¹ 5.42, 415, F (CDCl₃ andMeOD, 400 MHz): 8.80 (d, J = 2.2 Hz, 1 H); 8.74 (s, 1 H); 8.70 (d, J =2.2 Hz, 1 H); 3.69-3.60 (m, 6 H); 3.42 (s, 3 H); 2.94-2.87 (m, 4 H);2.79 (t, J = 5.45 Hz, 2 H). 298

  3-Bromo-5-[4-(2,2,2-trifluoro-ethyl)- piperazin-1-yl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D C, B¹ 4.60, 439, G (CDCl₃ and MeOD,300 MHz): 8.76 (d, J = 2.2 Hz, 1 H); 8.75 (s, 1 H); 8.69 (d, J = 2.2 Hz,1 H); 3.66-3.60 (m, 4 H); 3.25 (q, J = 9.6 Hz, 2 H); 3.10-3.04 (m, 4 H).299

  3-Bromo-5-[4-(2-methanesulfonyl- ethyl)-piperazin-1-yl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile D 2.45, 463, G

The compounds of the Examples in Table 15 were prepared via the generalMitsunobu or the general Bromide Displacement Methods followed by thegeneral reduction procedure described above.

TABLE 15 Puri- LCMS Ex- Bromide Depro- fication R_(T), M + am- MitsunobuDisplacement Reduction tection Meth- H⁺, ple Structure/Name MethodMethod Method Method od Method ¹H NMR (ppm) 300

  5-(Piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA A B C² 4.74, 294, F (MeOD andCDCl₃, 300 MHz): 8.73 (s, 1 H); 8.66 (s, 1 H); 8.65-8.63 (m, 1 H);7.46-7.41 (m, 1 H); 4.96-4.87 (m, 1 H); 3.21- 3.13 (m, 2 H); 2.72-2.62(m, 2 H); 2.23-2.13 (m, 2 H); 1.99-1.88 (m, 2 H). 301

  5-(1-Ethyl-piperidin-4-yloxy)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA A E B⁴ 5.10, 322, F (DMSO-D₆, 400 MHz): 12.94 (s, 1H);8.79 (s, 1 H); 8.71 (dd, J = 6.0, 1.7 Hz, 1 H); 8.60 (dd, J = 9.4, 1.7Hz, 1 H); 7.47 (dd, J = 12.5, 4.7 Hz, 1 H); 4.78- 4.66 (m, 1 H);2.90-2.78 (m, 2 H); 2.34 (q, J = 7.2 Hz, 2 H); 2.13-2.00 (m, 4 H);1.99-1.86 (m, 2 H); 1.00 (t, J = 7.2 Hz, 3 H). 302

  5-((S)-1-Ethyl-pyrrolidin-3-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile A NA B E B² 4.28, 308,F (DMSO-D₆, 400 MHz): 12.92 (s, 1 H); 8.78 (s, 1 H); 8.74-8.68 (m, 2 H);7.45 (dd, J = 7.9, 4.8 Hz, 1 H); 5.43-5.36 (m, 1 H); 3.05-2.94 (m, 2 H);2.71- 2.62 (m, 1 H); 2.57-2.42 (m, 2 H); 2.41-2.26 (m, 2 H); 2.21-2.09(m, 1 H); 1.06 (t, J = 7.2 Hz, 3 H). 303

  5-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile A NA B E C, Q² 4.88,320, F (DMSO-D₆, 300 MHz): 13.27-12.47 (br s, 1 H); 8.76 (s, 1 H); 8.70(dd, J = 4.8, 1.6 Hz, 1 H); 8.53 (dd, J = 7.9, 1.7 Hz, 1 H); 7.48 (dd, J= 7.9, 4.8 Hz, 1 H); 5.09-4.98 (m, 1 H); 3.11- 2.97 (m, 2 H); 2.89-2.54(s, 4 H); 2.26-2.18 (m, 1 H); 2.17-2.03 (m, 1 H); 1.76 (m, 1 H);1.56-1.39 (m, 2 H). 304

  5-(1-Isopropyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile A NA B E C, Q² 2.25,336, H (CDCl₃ and MeOD, 300 MHz): 8.74 (s, 1 H); 8.68-8.66 (m, 1 H);8.65 (s, 1 H); 7.46-7.40 (m, 1 H); 4.99-4.86 (m, 1 H); 3.05- 2.94 (m, 2H); 2.87-2.74 (m, 1 H); 2.50-2.38 (m, 2 H); 2.29-2.02 (m, 4 H); 1.11 (d,J = 6.6 Hz, 6 H). 305

  5-[1-(2-Methoxy-ethyl)-piperidin-4- yloxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA B E C, Q² 5.46, 352, F (CDCl₃ and MeOD, 300MHz): 8.74 (s, 1 H); 8.68-8.63 (m, 2 H); 7.45- 7.40 (m, 1 H); 5.00-4.86(m, 1 H); 3.57 (t, J = 5.5 Hz, 2 H); 3.37 (s, 3 H); 3.07- 2.97 (m, 2 H);2.66 (t, J = 5.55 Hz, 2 H); 2.44-2.31 (m, 2 H); 2.28-2.04 (m, 4 H). 306

  5-[(S)-(1-Aza-bicyclo[2.2.2]oct-3-yl) oxy]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA B E B¹ 5.02, 320, F (DMSO-D₆, 300 MHz):13.01 (br s, 1 H); 8.82 (d, J = 0.5 Hz, 1 H); 8.73 (dd, J = 4.8, 1.6 Hz,1 H); 8.56 (dd, J = 7.9, 1.6 Hz, 1 H); 7.49 (dd, J = 7.9, 4.8 Hz, 1 H);5.27-5.17 (m, 1 H); 4.14-3.99 (m, 1 H); 3.83- 3.69 (m, 1 H); 3.55-2.92(m, 5 H); 2.42-2.23 (m, 1 H); 1.97-1.62 (m, 3 H). 307

  5-(4-Ethyl-piperazin-1-yl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N A C A N A R⁷ 3.29, 307, F (CDCl₃ and CD₃OD, 400 MHz):8.86 (s, 1 H); 8.84 (dd, J = 8.0, 1.6 Hz, 1 H); 8.69 (dd, J = 4.8, 1.6Hz, 1 H); 7.50 (dd, J = 8.0, 4.8 Hz, 1 H); 4.01-3.76 (m, 4 H); 3.74-3.57(m, 4 H); 3.42 (q, J = 7.3 Hz, 2 H); 1.49 (t, J = 7.3 Hz, 3 H). 308

  5-(1-Ethyl-piperidin-4-ylamino)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N A C A N A R⁷ 4.27, 321, F (CDCl₃ and CD₃OD, 400 MHz):8.71 (d, J = 8.0 Hz, 1 H); 8.62 (dd, J = 4.9, 1.5 Hz, 1 H); 8.53 (s, 1H); 7.43 (dd, J = 8.0, 4.9 Hz, 1 H); 4.44-4.32 (m, 1 H); 3.74-3.61 (m, 2H); 3.27- 3.03 (m, 4 H); 2.56-2.41 (m, 2 H); 2.30-2.14 (m, 2 H); 1.42(t, J = 7.3 Hz, 3 H). 309

  5-(4-Diethylamino-piperidin-1-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6- carbonitrile N A D A N A R⁷ 5.05,349, F (CDCl₃ plus CD₃OD, 400 MHz): 8.78 (s, 1H), 8.72 (dd, J = 8.0, 1.5Hz, 1H), 8.66 (dd, J = 4.9, 1.8 Hz, 1H), 7.48 (dd, J = 8.0, 4.9 Hz, 1H),3.75-3.61 (m, 5H), 3.46-3.35 (m, 4H), 2.37-2.29 (m, 2H), 2.28-2.15 (m,2H), 1.44 (t, J = 7.3 Hz, 6H). 310

  5-[4-(2-Methoxy-ethyl)-piperazin-1-yl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole- 6-carbonitrile N A D A N A R⁷4.17, 337, F (CDCl₃ plus CD₃OD, 400 MHz): 8.84 (s, 1H), 8.80 (dd, J =8.0, 1.6 Hz, 1H), 8.68 (dd, J = 4.9, 1.6 Hz, 1H), 7.49 (dd, J = 8.0, 4.9Hz, 1H), 3.87-3.76 (m, 6H), 3.66-3.50 (m, 4H), 3.47 (s, 3H), 3.45-3.36(m, 2H). 311

  5-[4-(2,2,2-Trifluoro-ethyl)-piperazin-1-yl]-9H-dipyrido[2,3-b;4′,3′-d] pyrrole-6-carbonitrile N A D A N A R⁷10.56, 361, F (CDCl₃ plus CD₃OD, 400 MHz): 8.75 (s, 1H), 8.72 (dd, J =8.0, 1.6 Hz, 1H), 8.65 (dd, J = 6.3, 1.6 Hz, 1H), 7.45 (dd, J = 8.0, 4.9Hz, 1H), 3.66-3.60 (m, 4H), 3.24 (q, J = 9.7 Hz, 2H), 3.10-3.05 (m, 4H).312

  5-[4-(2-Methanesulfonyl-ethyl)- piperazin-1-yl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile N A D A N A R⁷ 4.53, 385, F (CDCl₃plus CD₃OD, 400 MHz): 8.77 (s, 1H), 8.74 (dd, J = 8.0, 1.6 Hz, 1H), 8.65(dd, J = 6.2, 1.6 Hz, 1H), 7.46 (dd, J = 8.0, 4.9 Hz, 1H), 3.73-3.62 (m,4H), 3.51-3.39 (m, 2H), 3.24-3.12 (m, 4H), 3.10-2.94 (m, 5H). 313

  trans-5-(-1-Ethyl-3-fluoro- piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile A NA A E R⁵ 4.73, 340, F (CDCl₃plus CD₃OD, 300 MHz): 8.75 (s, 1H), 8.69 (dd, J = 7.9, 1.6 Hz, 1H), 8.63(dd, J = 4.9, 1.6 Hz, 1H), 7.38 (dd, J = 7.9, 4.9 Hz, 1H), 5.15-4.74 (m,2H), 3.36-3.23 (m, 1H), 3.04- 2.94 (m, 1H), 2.62-2.35 (m, 3H), 2.28-2.04(m, 3H), 1.13 (t, J = 7.2 Hz, 3H).

Example 3145-Bromo-6-chloro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1: 5-Bromo-6-chloro-4-iodonicotinic acid

n-Butyllithium (1.6M in hexanes, 172 mL, 276 mmol) was added to asolution of 2,2,6,6-tetramethylpiperidine (48.5 mL, 285 mmol) inanhydrous THF (200 mL) at −50° C. After 20 min, solid5-bromo-6-chloronicotinic acid (21.6 g, 92 mmol) was added portionwiseand the resultant slurry was allowed to warm to −20° C. over 1 h andstirred at that temperature for 1 h. After this time, the reactionmixture was cooled to −60° C. and transferred via cannula to a solutionof iodine (70 g, 276 mmol) in anhydrous THF (100 mL) at −60° C. at sucha rate that the internal temperature of the solution remained below −40°C. On complete addition, the reaction mixture was allowed to warm slowlyto ambient temperature and stirred for 18 h. The reaction mixture wasconcentrated in vacuo and the resultant dark red slurry was dissolved inwater (500 mL) and washed with diethyl ether (3×200 mL). The pH ofaqueous layer was adjusted to 2 by the addition of 1M aqueoushydrochloric acid and the resulting beige precipitate was collected byfiltration and dried under vacuum to afford the title compound (17.7 g,53%). ¹H NMR (DMSO-D₆, 400 MHz): 8.30 (s, 1H).

Step 2: (5-Bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butylester

Triethylamine (20.6 mL, 147 mmol) was added to a solution of5-bromo-6-chloro-4-iodo-nicotinic acid (17.7 g, 49 mmol) anddiphenylphosphorazide (15.8 mL, 73 mmol) in toluene (100 mL) and t-BuOH(90 mL) and the resultant solution was heated at 110° C. for 3 h. Thereaction mixture was allowed to cool and then concentrated in vacuo andthe resultant residue was purified by flash chromatography (silica, 330g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the titlecompound as a white solid (21.1 g, 90%). ¹H NMR (DMSO-D₆, 400 MHz): 9.04(s, 1H), 8.25 (s, 1H), 1.47 (s, 9H).

Step 3: 5-Bromo-6-chloro-4-iodo-pyridin-3-ylamine

Trifluoroacetic acid (30 mL) was added to a solution of(5-bromo-6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester(19.0 g, 44 mmol) in DCM (120 mL) and the resultant solution was stirredat ambient temperature for 2 h then concentrated in vacuo. The resultantresidue was loaded onto an SCX-2 cartridge (70 g) eluting withacetonitrile (100 mL) then 2N ammonia in methanol (100 mL). The basicfraction was concentrated in vacuo to afford the title compound (11.5 g,78%). ¹H NMR (DMSO-D₆, 400 MHz): 7.23 (s, 1H), 5.92 (s, 2H).

Step 4: 2-Fluoro-5-(4-piperidin-1-ylmethylphenyl)-pyridine

A degassed mixture of 5-bromo-2-fluoropyridine (578 μL, 5.60 mmol),4-piperidin-1-ylmethyl-boronic acid (1.23 g, 5.6 mmol),1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (205 mg, 5mol %) in 1N potassium fluoride solution (4 mL) and acetonitrile (9 mL)was heated under microwave irradiaition at 100° C. for 15 min. Theresultant crude mixture was diluted with water (10 mL) and extractedwith DCM (3×20 mL). The combined organic layer was purified by flashchromatography (silica, 40 g column, ISCO, 0-10% (2N ammonia in MeOH) inDCM) to afford the title compound (1.27 g, 84%). ¹H NMR (CDCl₃, 400MHz): 8.41 (d, J=2.5 Hz, 1H), 7.96 (td, J=8.5, 2.5 Hz, 1H), 7.48 (d,J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 6.99 (dd, J=8.5, 3.0 Hz, 1H),3.52 (s, 2H), 2.40 (br. s, 4H), 1.59 (p, J=6.0 Hz, 4H), 1.44 (t, J=6.0Hz, 2H). LCMS (Method B): R_(T)=2.05 min, M+H⁺=271.

Step 5: 2-Fluoro-3-boronicacid-5-(4-piperidin-1-ylmethylphenyl)-pyridine

Lithium diisopropylamine (7.1 mL, 14.1 mmol) was added to a solution of2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-pyridine (1.27 g, 4.70 mmol)and triisopropyl borate (3.26 mL, 14.1 mmol) in anhydrous THF (12 mL) at−10° C. The resultant solution was stirred between −10° C. and 0° C. for1 h, and then quenched by the addition of saturated aqueous ammoniumchloride (10 mL). The reaction mixture was diluted with water (20 mL)and extracted with DCM (3×20 mL). The combined organic layer was driedover magnesium sulfate and concentrated in vacuo. The crude oil wastriturated with cyclohexane:DCM (3:1) to afford the title compound as abeige solid (677 mg, 46%). NMR (DMSO-D₆, 300 MHz): 8.53 (s, 1H),8.35-8.31 (m, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H),3.54-3.42 (m, 2H), 2.44-2.24 (m, 4H), 1.57-1.45 (m, 4H), 1.44-1.36 (m,2H), 1.20 (d, J=6.5 Hz, 2H). LCMS (Method B): R_(T)=1.79 min, M+H⁺=315.

Step 6:5′-Bromo-6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine

A mixture of 2-fluoro-3-boronicacid-5-(4-piperidin-1-ylmethylphenyl)-pyridine (515 mg, 1.6 mmol),5-bromo-6-chloro-4-iodo-pyridin-3-ylamine (546 mg, 1.6 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloro palladium(II) (60 mg, 5mol %) in 1N potassium fluoride solution (5 mL) and acetonitrile (15 mL)was heated under microwave irradiation at 110° C. for 20 min. Thereaction mixture was allowed to cool to ambient temperature, dilutedwith water (10 mL) and extracted with DCM (3×20 mL). The combinedorganic layer was concentrated in vacuo and the residue was purified byflash chromatography (silica, 12 g column, ISCO, 0-10% MeOH in DCM) toafford the title compound (189 mg, 24%). ¹H NMR (CDCl₃, 300 MHz): 8.57(dd, J=2.5, 1.0 Hz, 1H), 7.96 (s, 1H), 7.90 (dd, J=8.5, 2.5 Hz, 1H),7.53 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 3.72 (s, 2H), 3.54 (s,2H), 2.41 (br. s, 4H), 1.64-1.58 (m, 4H), 1.48-1.44 (m, 2H). LCMS(Method B): R_(T)=2.41 min, M+H⁺=475/477.

Step 7:5-Bromo-6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Sodium bis(trimethylsilyl)amide (3.9 mL, 3.90 mmol) was added to asolution of5′-bromo-6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine(187 mg, 0.39 mmol) in anhydrous THF (7.0 mL) and the resultant solutionstirred at ambient temperature for 20 min. The reaction mixture wasdiluted with water (20 mL) and extracted with DCM: MeOH (4:1, 3×20 mL).The combined organic layer was dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The resultant residue was purifiedby flash chromatography (silica, 4 g column, ISCO, 0-15% MeOH in DCM) toafford the title compound as a beige powder (30 mg, 17%). ¹H NMR (CDCl₃,400 MHz): 9.17 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.67 (s, 1H),7.65 (d, J=7.5 Hz, 2H), 7.49 (d, J=7.5 Hz, 2H), 3.59 (s, 2H), 2.51-2.47(m, 4H), 1.68-1.59 (m, 4H), 1.51-1.45 (m, 2H). LCMS (Method A):R_(T)=7.10 min, M+H+=455/457.

Example 3156-Chloro-3-(4-piperidin-1-ylmethyl-phenyl)-5-vinyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6′-Chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-5′-vinyl-[3,4]bipyridinyl-3′-ylamine

A mixture of5′-bromo-6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine(93 mg, 0.19 mmol), vinyltributyl tin (63 μL, 0.21 mmol),tetrakis(triphenylphosphine)palladium(0) (11 mg, 5 mol %) and lithiumchloride (25 mg, 0.59 mmol) in 1,4-dioxane (1.0 mL) was heated underreflux for 3.5 h. The reaction mixture was allowed to cool to ambienttemperature, diluted with water (10 mL) and extracted with DCM (3×20mL). The combined organic layer was concentrated in vacuo and theresultant residue purified by flash chromatography (silica, 4 g column,ISCO, 0-10% MeOH in DCM) to afford the title compound as a beige powder(77 mg, 82%). ¹H NMR (CDCl₃, 400 MHz): 8.50 (dd, J=2.5, 1.0 Hz, 1H),7.94 (s, 1H), 7.88 (dd, J=8.5, 2.5 Hz, 1H), 7.54-7.47 (m, 4H), 6.53 (dd,J=18.0, 11.5 Hz, 1H), 5.37 (dd, J=11.5, 1.0 Hz, 1H), 5.11 (dd, J=18.0,1.0 Hz, 1H), 3.60 (s, 2H), 3.55-3.50 (m, 2H), 2.48-2.35 (m, 4H),1.68-1.58 (m, 4H), 1.50-1.44 (m, 2H). LCMS (Method B): R_(T)=2.32 min,M+H⁺=423/425.

Step 2:6-Chloro-3-(4-piperidin-1-ylmethyl-phenyl)-5-vinyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Sodium bis(trimethylsilyl)amide (1.3 mL, 1.3 mmol) was added to asolution of6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-5′-vinyl-[3,4]bipyridinyl-3′-ylamine (53 mg, 0.13 mmol) in anhydrous THF (1 mL) andthe resultant solution stirred at ambient temperature for 20 min. Thereaction mixture was diluted with brine (5 mL) and ethyl acetate (5 mL).The resultant precipitate was collected by filtration to afford thetitle compound as a beige powder (13 mg, 26%). NMR (CDCl₃, 400 MHz):8.85 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.61 (s, 1H), 7.58-7.55(m, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.22-7.14 (m, 1H), 6.03-6.01 (m, 1H),5.99-5.97 (m, 1H), 3.56 (s, 2H), 2.47-2.37 (m, 4H), 1.64-1.59 (m, 4H),1.52-1.44 (m, 2H). LCMS (Method A): R_(T)=6.81 min, M+H⁺=403/405.

Example 3165-Ethyl-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1: Trifluoromethanesulfonic acid9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yl ester

Trifluoromethanesulfonic anhydride (0.91 g, 0.54 mL, 3.22 mmol) wasadded dropwise to a suspension of9-benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(1.03 g, 2.93 mmol) in pyridine (1.2 mL, 14.7 mmol) and dry DCM (20 mL)at 0° C. The reaction mixture was then allowed to warm to ambienttemperature and stirred for 2 h. The reaction mixture was treated with1N hydrochloric acid (10 mL) and the phases were separated. The aqueousphase was extracted with DCM (2×10 mL), the combined organic phase wasdried over anhydrous magnesium sulfate and concentrated in vacuo. Theresultant residue was purified by chromatography (silica, 5 g column,Si-SPE, DCM) to afford the title compound as a white solid (855 mg,60%). LCMS (Method B): R_(T)=4.22 min, M+H⁺=483.

Step 2:9-Benzenesulfonyl-5-vinyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of trifluoromethanesulfonic acid9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yl ester(150 mg, 0.31 mmol), tributyl(vinyl)stannane (102 μL, 0.35 mmol),lithium chloride (40 mg, 0.93 mmol) andtetrakis(triphenylphosphine)palladium(0) (7.0 mg, 6.0 μmol) in dioxane(1.5 mL) was degassed with argon and heated under reflux for 18 h. Thereaction mixture was allowed to cool to ambient temperature then dilutedwith DCM (9 mL) and methanol (1 mL). The resultant residue was purifiedby chromatography (silica, 2 g column, Si-SPE, 0-2% MeOH in DCM) andtriturated with pentane (2×2 mL) to afford the title compound as a whitesolid (60 mg, 52%). LCMS (Method B): R_(T)=3.73 min, M+H⁺=361.

Step 3:9-Benzenesulfonyl-5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of9-benzenesulfonyl-5-vinyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(60 mg 0.16 mmol) and 10% palladium on carbon (20 mg) in THF (4 mL) andIMS (3 mL) was stirred under an atmosphere of hydrogen for 3 h. Thereaction vessel was then purged with nitrogen then the reaction mixturewas filtered through celite. The celite pad was washed with DCM and thenethyl acetate and the combined filtrate was concentrated in vacuo toyield the title compound as a beige solid (60 mg, 99%). LCMS (Method B):R_(T)=3.78 min, M+H⁺=363.

Step 4: 5-Ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of9-benzenesulfonyl-5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(60 mg, 0.16 mmol), DCM (3.0 mL) and 7N ammonia in methanol (3 mL) wasstirred at room temperature for 5 days. The reaction mixture was thenconcentrated in vacuo and the resultant residue was triturated withmethanol (2 mL) and dried in vacuo to give the title compound as anoff-white solid (28 mg, 81%). LCMS (Method B): R_(T)=2.81 min, M+H⁺=223.

Step 5: 3-Bromo-5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

To a solution of5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (48 mg, 0.21mmol) in DMF (1 mL) was added NBS (54 mg, 0.30 mmol) then the reactionmixture was stirred for 18 h at ambient temperature. The reactionmixture was then diluted with ethyl acetate (20 mL) and washed withsaturated aqueous sodium carbonate (10 mL). The aqueous phase was washedwith DCM (2×10 mL), the combined organic phase was washed with saturatedbrine (2×10 mL) and concentrated in vacuo to afford the title compoundas a yellow solid (50 mg, 79%). LCMS (Method B): R_(T)=3.34 min,M+H⁺=301/303.

Step 6:5-Ethyl-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of3-bromo-5-ethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (48 mg,0.16 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (56 mg, 0.26mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12mg, 0.016 mmol) in 2N aqueous sodium carbonate (0.5 mL) and acetonitrile(0.63 mL) was heated under microwave irradiation at 140° C. for 35minutes. The reaction mixture was allowed to cool to ambienttemperature, diluted with water (5 mL) and extracted with ethyl acetate(3×5 mL). The combined organic layer was dried over anhydrous magnesiumsulfate, filtered and evaporated in vacuo. The resultant residue waspurified by flash chromatography (silica, 2 g column, ISCO, 0-5%methanol in DCM) and trituration with diethyl ether (2×1 mL) to affordthe title compound as a beige solid (29 mg, 46%). ¹H NMR (DMSO-D₆, 400MHz): 12.93 (br. s, 1H), 8.99 (d, J=2.2 Hz, 1H), 8.91 (s, 1H), 8.79 (d,J=2.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 3.53-3.43(m, 4H), 2.42-2.33 (m, 4H), 1.55-1.47 (m, 4H), 1.46-1.37 (m, 5H). LCMS(Method A): R_(T)=6.23 min, M+H⁺=396.

Example 3175-Hydroxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1: 9-Benzenesulfonyl-5-hydroxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(150 mg, 0.35 mmol), 4-piperidin-1-ylmethylphenyl boronic acid (126 mg,0.6 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27 mg, 0.04 mmol) in 2N aqueouspotassium acetate (1.1 mL) and acetonitrile (1.4 mL) was heated undermicrowave irradiation at 140° C., for 30 minutes. The reaction mixturewas diluted with ethyl acetate (10 mL) and water (10 mL) resulting inthe formation of a precipitate. The supernatant liquors were decantedand the precipitate was dissolved in 10% methanol in DCM. The decantedliquors were partitioned and the aqueous phase was washed with 10%methanol in DCM (2×10 mL). The combined organic phases were concentratedin vacuo and the resultant residue purified by column chromatography(silica, 2 g cartridge, Si-SPE, 0-20% MeOH in DCM) afforded the crudeproduct which was triturated with acetonitrile (1 mL) and methanol (1mL) to afford the title compound as a beige solid (60 mg, 31%). LCMS(Method B): R_(T)=2.65 min, M+H⁺=524.

Step 2:5-Hydroxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile

9-Benzenesulfonyl-5-hydroxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(50 mg, 0.01 mmol) was dissolved in 0.15N potassium hydroxide solutionin methanol (7 mL). The reaction mixture was stirred for 2.5 h thentreated with a solution of monobasic potassium phosphate (136 mg, 1.0mmol) in water (2 mL). The resultant mixture was concentrated in vacuoand the resultant residue was diluted with water (5 mL). The pH of theaqueous phase was adjusted to 7 by the addition of 1N hydrochloric acid.The aqueous phase was extracted with ethyl acetate, DCM and THF. Thecombined organic phase was concentrated in vacuo and the residuepurified by flash chromatography (silica, 500 mg column, Si-SPE, 10-20%methanol in DCM) to afford the title compound as its hydrochloride salt(25 mg, 63%). NMR (DMSO-D₆, 400 MHz): 12.91 (s, 1H), 11.86 (br. s, 1H),10.41 (s, 1H), 9.13 (d, J=2.2 Hz, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.60 (s,1H), 7.93 (d, J=8.1 Hz, 2H), 7.76 (d, J=8.1 Hz, 2H), 4.33 (d, J=5.2 Hz,2H), 3.39-3.29 (m, 2H), 2.92-2.83 (m, 2H), 1.85-1.63 (m, 5H), 1.45-1.31(m, 1H). LCMS (Method A): R_(T)=5.32 min, M+H⁺=384.

Example 3185-Ethoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrilehydrochloride

Step 1:9-Benzenesulfonyl-3-bromo-5-ethoxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(120 mg, 0.28 mmol) in anhydrous THF (5 mL) was cooled to 0° C. andtreated with sodium hydride (60% dispersion in mineral oil; 12 mg, 0.30mmol). After gas evolution had ceased, iodoethane (424 μL, 4.10 mmol)was added and the mixture stirred at ambient temperature overnight thenheated at 60° C. for 5 h. The reaction was then allowed to cool, dilutedwith toluene and concentrated in vacuo. The residue was purified bycolumn chromatography (silica, 2 g column, Si II SPE, 10-100% ethylacetate in DCM) to afford the title compound as a yellow solid (30 mg,23%). ¹H NMR (DMSO-D₆, 400 MHz): 8.86 (s, 1H), 8.77 (s, 2H), 8.24-8.22(m, 1H), 8.22-8.20 (m, 1H), 7.81-7.75 (m, 1H), 7.68-7.61 (m, 2H), 4.75(q, J=7.2 Hz, 2H), 1.64 (t, J=7.2 Hz, 3H). LCMS (Method B): R_(T)=3.30min, M+H⁺=457/459.

Step 2:5-Ethoxy-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrilehydrochloride

A degassed mixture of9-benzenesulfonyl-3-bromo-5-ethoxy-9H-dipyrido[2,3-b;4′,3′d]pyrrole-6-carbonitrile (60 mg, 0.13 mmol),4-piperidin-1-ylmethylphenyl boronic acid (48 mg, 0.22 mmol) and[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (10 mg,0.013 mmol) in 2N aqueous sodium carbonate (0.42 mL) and acetonitrile(0.53 mL) was heated under microwave irradiation at 140° C. for 30minutes. The reaction mixture was allowed to cool to ambienttemperature, diluted with ethyl acetate (5 mL) and THF (5 mL) and washedwith sodium hydrogen carbonate (5 mL). The aqueous phase was extractedwith THF (2×5 mL) then the combined organic layer was concentrated invacuo. The resultant residue was taken up in 1:1 DCM:MeOH containing 0.5mL 1M hydrochloric acid and purified by flash chromatography (silica, 2g column, Si-SPE, 5-25% methanol in DCM) and trituration withacetonitrile and 20% MeOH in acetonitrile to afford the title compoundas the hydrochloride salt as a brown powder (24 mg, 41%). ¹H NMR(DMSO-D₆, 400 MHz): 8.98 (d, J=2.3 Hz, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.44(s, 1H), 7.84 (d, J=7.8 Hz, 2H), 7.62 (d, J=7.8 Hz, 2H), 4.64 (q, J=7.2Hz, 2H), 4.34 (s, 2H), 3.54-3.45 (m, 4H), 3.44-3.26 (m, 1H), 3.02-2.82(m, 2H), 1.91-1.66 (m, 4H), 1.62 (t, J=7.2 Hz, 3H). LCMS (Method A):R_(T)=4.94 min, M+H⁺=412.

Example 3195-(2-Methoxyethoxy)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:9-Benzenesulfonyl-3-bromo-5-(2-methoxy-ethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(120 mg, 0.28 mmol), 2-methoxyethanol (128 μL, 1.60 mmol) andtriphenylphosphine (315 mg, 1.60 mmol) in anhydrous DMF (1.25 mL) wastreated dropwise with diethyl azodicarboxylate (252 μL, 1.60 mmol) andthe mixture stirred at ambient temperature for 9 h. The mixture wasdiluted with ethyl acetate (15 mL) and washed with brine (3×10 mL),dried over anhydrous magnesium sulfate, filtered and evaporated invacuo. The crude material was purified by column chromatography (silica,5 g column, Si-SPE, 30-50% DCM in pentane) to afford the title compound(50 mg, 37%). ¹H NMR (CDCl₃, 400 MHz): 9.58 (s, 1H), 8.97 (d, J=2.3 Hz,1H), 8.76 (d, J=2.3 Hz, 1H), 8.24-8.22 (m, 1H), 8.22-8.00 (m, 1H),7.66-7.60 (m, 1H), 7.54-7.48 (m, 2H), 4.74-4.69 (m, 2H), 3.87-3.83 (m,2H), 3.48 (s, 3H). LCMS (Method B): R_(T)=4.25 min, M+H⁺=487/489.

Step 2:5-(2-Methoxyethoxy)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A degassed mixture of3-bromo-5-(2-methoxy-ethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(50 mg, 0.10 mmol), 4-piperidin-1-ylmethylphenyl boronic acid (31 mg,0.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)(9 mg, 0.012 mmol) in 2N aqueous sodium carbonate solution (0.42 mL) andacetonitrile (0.53 mL) were heated under microwave irradiation at 140°C. for 30 minutes. The reaction mixture was diluted with water (2 mL)and extracted with 10% MeOH in DCM. The combined organic phase wasconcentrated in vacuo and the resultant residue was purified by flashchromatography (silica, 500 mg column, Si-SPE, 0-20% methanol in DCM).The resultant residue was dissolved in a solution of 0.15M potassiumhydroxide in methanol (7 mL) and stirred for 45 minutes. 1N Potassiumdihydrogen phosphate (1 mL) was added then the mixture concentrated invacuo. The resultant residue was diluted with water and the pH adjustedto 7 by the addition of 1N potassium dihydrogen phosphate. The aqueousphase was extracted with DCM (3×10 mL) and 20% ethanol in DCM (10 mL),the combined organic phase was dried over magnesium sulfate andconcentrated in vacuo. The resultant residue was purified by flashchromatography (silica, 500 mg column, Si-SPE, 2-4% methanol in DCM) andtrituration with acetonitrile to afford the title compound as a brownsolid (14 mg, 32%). ¹H NMR (CDCl₃, 300 MHz): 9.91 (s, 1H), 9.09 (d,J=2.2 Hz, 1H), 8.93 (d, J=2.2 Hz, 1H), 8.80 (s, 1H), 7.67 (d, J=8.1 Hz,2H), 7.49 (d, J=8.0 Hz, 2H), 4.75-4.69 (m, 2H), 3.95-3.89 (m, 2H), 3.58(s, 2H), 3.47 (s, 3H), 2.51-2.37 (m, 4H), 1.68-1.54 (m, 4H), 1.52-1.41(m, 2H). LCMS (Method A): R_(T)=6.27 min, M+H⁺=442.

Example 3203-(1-Methyl-1H-pyrazol-4-yl)-5-(pyrrolidin-3-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrilehydrochloride

Step 1:3-(9-Benzenesulfonyl-3-bromo-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yloxy)pyrrolidine-1-carboxylicacid tert-butyl ester

A solution of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(200 mg, 0.46 mmol), 3-hydroxypyrrolidine-1-carboxylic acid tert-butylester (670 mg, 3.56 mmol) and triphenylphosphine (724 mg, 2.76 mmol) inanhydrous DMF (2 mL) was treated dropwise with diethyl azodicarboxylate(0.53 mL, 3.40 mmol) and the mixture stirred at ambient temperature for3 h then left to stand overnight. The mixture was diluted with ethylacetate (20 mL) and washed with brine (3×15 mL), dried over magnesiumsulfate and concentrated in vacuo. The crude material was purified byflash chromatography (silica, 20 g column, Si-SPE, 0-20% methanol inDCM). Collecting appropriate fractions afforded the title compound (160mg, 57%). NMR (CDCl₃, 400 MHz): 9.57 (s, 1H), 8.76 (d, J=2.3 Hz, 1H),8.46 (d, J=2.3 Hz, 1H), 8.24-8.23 (m, 1H), 8.23-8.21 (m, 1H), 7.71-7.61(m, 1H), 7.58-7.45 (m, 2H), 5.88-5.83 (m, 1H), 4.36-4.11 (m, 1H),3.87-3.36 (m, 2H), 2.48-2.26 (m, 2H), 2.13-2.05 (m, 1H), 1.46 (s, 9H).LCMS (Method B): R_(T)=4.51 min, M+H⁺=598/600.

Step 2:3-[6-Cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester

A degassed mixture of3-(3-bromo-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (160 mg, 0.20 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(54 mg, 0.26 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg,0.026 mmol) in 1N aqueous potassium fluoride (0.60 mL, 0.60 mmol) andacetonitrile (0.60 mL) was heated at 130° C. under microwave irradiationfor 30 minutes. The reaction mixture was allowed to cool to ambienttemperature diluted with water (5 mL) and saturated aqueous sodiumcarbonate (5 mL) then extracted with ethyl acetate (3×10 mL). Thecombined organic phase was dried over magnesium sulfate and concentratedin vacuo. The resultant was purified by flash chromatography (silica, 2g column, Si-SPE cartridge, 0-100% ethyl acetate in DCM then methanol)and trituration with acetonitrile to afford the title compound as awhite solid (28 mg, 30%). ¹H NMR (CDCl₃, 400 MHz): 8.78-8.71 (m, 2H),8.46 (s, 1H), 7.90 (s, 1H), 7.85-7.80 (m, 1H), 5.81 (s, 0.5H), 5.73 (s,0.5H), 4.01 (s, 3H), 3.86-3.57 (m, 3H), 2.58-2.40 (m, 1H), 2.37-2.17 (m,2H), 1.39 (s, 4H), 1.33 (s, 5H). LCMS (Method B): R_(T)=3.09 min,M+H⁺=460.

Step 3:3-(1-Methyl-1H-pyrazol-4-yl)-5-(pyrrolidin-3-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile,hydrochloride salt

3-[6-Cyano-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester (28 mg, 0.06 mmol) was treated with a mixture ofacetyl chloride and methanol (2:5, 1 mL). After 1 h the mixture wasconcentrated in vacuo and the resultant residue was triturated withacetonitrile, the solid collected by filtration and dried in vacuo toafford the compound as a yellow solid (25 mg, 100%). ¹H NMR (DMSO-D₆,400 MHz): 13.07 (s, 1H), 9.83 (s, 1H), 9.63 (s, 1H), 8.99 (d, J=2.1 Hz,1H), 8.82 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.45 (s, 1H), 8.11 (d, J=0.8Hz, 1H), 5.68-5.61 (m, 1H), 3.98-3.88 (m, 5H), 3.62-3.43 (m, 2H),2.43-2.34 (m, 1H), 2.29-2.17 (m, 1H). LCMS (Method A): R_(T)=4.97 min,M+H⁺=360.

Example 3213-(1-Methyl-1H-pyrazol-4-yl)-5-(S)-pyrrolidin-3-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrileHydrochloride salt

The title compound was prepared using the procedure described in Example320 using (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester.¹H NMR (DMSO-D₆, 400 MHz): 13.06 (s, 1H), 9.67 (s, 1H), 9.43 (s, 1H),8.99 (d, J=2.1 Hz, 1H), 8.82 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.41 (s,1H), 8.09 (d, J=0.8 Hz, 1H), 5.68-5.60 (m, 1H), 3.99-3.89 (m, 4H),3.80-3.70 (m, 1H), 2.44-2.34 (m, 1H), 2.30-2.17 (m, 1H). LCMS (MethodA): R_(T)=5.07 min, M+H⁺=360.

Example 3223-(1-Methyl-1H-pyrazol-4-yl)-5-((R)-pyrrolidin-3-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile,hydrochloride salt

The title compound was prepared using the procedure described in Example320 using (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester.¹H NMR (DMSO-D₆, 400 MHz): 13.07 (s, 1H), 9.83 (s, 1H), 9.63 (s, 1H),8.99 (d, J=2.1 Hz, 1H), 8.82 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.45 (s,1H), 8.11 (d, J=0.8 Hz, 1H), 5.68-5.61 (m, 1H), 3.98-3.88 (m, 5H),3.62-3.43 (m, 2H), 2.43-2.34 (m, 1H), 2.29-2.17 (m, 1H). LCMS (MethodA): R_(T)=4.97 min, M+H⁺=360.

Example 3235-(2-Methoxyethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:9-Benzenesulfonyl-3-bromo-5-(2-methoxyethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(145 mg, 0.3 mmol), 2-methoxyethanol (158 μL, 2.0 mmol) andtriphenylphosphine (525 mg, 2.0 mmol) in anhydrous DMF (1.25 mL) wastreated with diethyl azodicarboxylate (0.315 mL, 2.0 mmol) and themixture stirred at ambient temperature for 30 min then left to stand for4 days. The mixture was diluted with ethyl acetate (20 mL) and washedwith brine (3×10 mL) then the aqueous phase was extracted with ethylacetate (10 mL). The combined organic phase was dried over magnesiumsulfate and concentrated in vacuo. The resultant residue was purified byflash chromatography (silica, 5 g column, Si-SPE, 0-100% ethyl acetatein DCM) to afford the title compound (35 mg, 23%). ¹H NMR (CDCl₃, 300MHz): 9.58 (s, 1H), 8.97 (d, J=2.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H),8.26-8.18 (m, 2H), 7.68-7.60 (m, 1H), 7.57-7.47 (m, 2H), 4.74-4.69 (m,2H), 3.89-3.80 (m, 2H), 3.49 (s, 3H).

Step 2:5-(2-Methoxyethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of9-benzenesulfonyl-3-bromo-5-(2-methoxyethoxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(35 mg, 0.07 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(20 mg, 0.096 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg) in 1N aqueous potassium fluoridesolution (0.30 mL) and acetonitrile (0.30 mL) was degassed and heatedunder microwave irradiation at 130° C. for 30 minutes. The reactionmixture was allowed to cool to ambient temperature and ethyl acetate (5mL) added. The solid was collected by filtration, washed with water (5mL) and acetonitrile (5 mL) and left to air dry. The resultant solid waspurified by flash chromatography (silica, 500 mg column, Si-SPE, 10%MeOH in DCM) and trituration with acetonitrile (2×0.25 mL) to afford thetitle compound as a grey solid (12 mg, 50%). ¹H NMR (DMSO-D6, 400 MHz):12.91 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (s,1H), 8.27 (s, 1H), 7.98 (s, 1H), 4.66-4.62 (m, 2H), 3.92 (s, 3H),3.87-3.83 (m, 2H), 3.36 (s, 3H). LCMS (Method A): R_(T)=7.66 min,M+H⁺=349.

Example 3243-(1-Methyl-1H-pyrazol-4-yl)-5-(piperidin-4-ylsulfanyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrileStep 1:5-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of9-benzenesulfonyl-5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-bipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(575 mg, 1.2 mmol) and tetrabutylammonium fluoride (1.0M in THF, 25 mL,25 mmol) in THF (25 mL) was stirred at ambient temperature for 15 min.The reaction mixture was evaporated in vacuo to afford a residue thatwas suspended in water and sonicated. The resultant solid was collectedby filtration and triturated with methanol to afford the title compoundas a white solid (420 mg, 100%). ¹H NMR (DMSO-D₆, 300 MHz): 9.02 (d,J=2.2 Hz, 1H), 8.98 (s, 1H), 8.93 (d, J=2.2 Hz, 1H), 8.33 (s, 1H), 8.02(s, 1H), 3.92 (s, 3H).

Step 2:5-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

To a solution of5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(547 mg, 1.55 mmol) in DMF (25 ml) under a flow of nitrogen was addedsodium hydride (93 mg, 60% dispersion in mineral oil, 2.39 mmol). After20 min, a yellow solution had formed and(2-chloromethoxyethyl)-trimethyl-silane (358 μL, 2.02 mmol) was added.The reaction mixture was stirred at ambient temperature for 3 days, thendiluted with water and sonicated. The resultant solid was collected byfiltration and triturated with methanol to afford the title compound asa yellow solid (404 mg, 54%). ¹H NMR (CDCl₃, 300 MHz): δ 9.13 (s, 1H),9.04 (d, J=2.2 Hz, 1H), 8.95 (d, J=2.1 Hz, 1H), 7.93-7.88 (m, 1H),7.83-7.77 (m, 1H), 6.06 (s, 2H), 4.06 (s, 3H), 3.70-3.59 (m, 2H),1.03-0.92 (m, 2H), −0.03 (s, 9H).

Step 3:4-[6-Cyano-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylsulfanyl]-piperidine-1-carboxylicacid tert-butyl ester

To a degassed suspension of5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(120 mg, 0.25 mmol), 4-mercaptopiperidine-1-carboxylic acid tert-butylester (54 mg, 0.25 mmol) and sodium tert-butoxide (26.4 mg, 0.28 mmol)in dimethoxyethane (0.4 mL) in a sealed 5 ml microwave vial was added adegassed solution of palladium(II) acetate (2.2 mg, 0.01 mmol) and(R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(5.5 mg, 0.01 mmol) in dimethoxyethane (1.0 mL). The reaction mixturewas heated at 100° C. for 22 h then cooled to ambient temperature andconcentrated in vacuo. The resultant residue was adsorbed onto HM-N thenpurified by flash chromatography (silica, 50 g column, Si-SPE, 0-10% (2Mammonia in MeOH) in DCM) to afford the title compound as a yellow solid(106 mg, 68%). ¹H NMR (DMSO-D₆, 300 MHz): 9.33 (s, 1H), 9.11-9.06 (m,2H), 8.35 (s, 1H), 8.05-8.01 (m, 1H), 6.05 (s, 2H), 3.93 (s, 3H),3.86-3.73 (m, 2H), 3.64-3.53 (m, 2H), 2.97-2.78 (m, 3H), 1.97-1.83 (m,2H), 1.64-1.45 (m, 2H), 1.35 (s, 9H), 0.87-0.78 (m, 2H), −0.17 (s, 9H).

Step 4:3-(1-Methyl-1H-pyrazol-4-yl)-5-(piperidin-4-ylsulfanyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of4-[6-cyano-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylsulfanyl]-piperidine-1-carboxylicacid tert-butyl ester (106 mg, 0.17 mmol) and trifluoroacetic acid (1mL) in dichloromethane (9 mL) was stirred at ambient temperature for 22h. The reaction mixture was concentrated in vacuo and the resultantresidue partitioned between dichloromethane (10 mL) and a saturatedaqueous solution of sodium hydrogen carbonate (10 mL). The organic phasewas concentrated in vacuo and the residue was adsorbed onto HM-N thenpurified by flash chromatography (silica, 25 g column, Si-SPE, 0-13% (2Mammonia in MeOH) in DCM) to afford the title compound as a pale yellowsolid (21.5 mg, 25%). ¹H NMR (DMSO-D₆, 300 MHz): 9.04 (d, J=2.2 Hz, 1H),9.02-8.97 (m, 2H), 8.29 (s, 1H), 7.98 (s, 1H), 3.93 (s, 3H), 3.54-3.21(m, 1H), 2.97-2.86 (m, 2H), 2.49-2.36 (m, 2H), 1.89-1.77 (m, 2H),1.65-1.47 (m, 2H). LCMS (Method F): R_(T)=7.08 min, M+H⁺=390.

Example 3255-(1-Ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:9-Benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A suspension of9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(5.0 g, 11.7 mmol) and 10% palladium on carbon (500 mg) in industrialmethylated spirits (120 mL), ethyl acetate (25 mL), dimethylformamide(25 mL) and triethylamine (25 mL) was stirred at ambient temperatureunder an atmosphere of hydrogen for 20 h. The reaction vessel was purgedwith nitrogen then the reaction mixture was filtered through celite. Thefiltrate was evaporated in vacuo. The resultant brown residue wassuspended in aqueous hydrochloric acid (1M, 40 mL) and sonicated for 20minutes then filtered to afford the title compound as a beige solid (4.0g, 98%). ¹H NMR (DMSO-D₆, 300 MHz): 9.27 (d, J=0.8 Hz, 1H), 8.73-8.65(m, 2H), 8.19 (d, J=7.9 Hz, 2H), 7.78-7.69 (m, 1H), 7.65-7.54 (m, 3H).

Step 2: 1,1,2,2,3,3,4,4,4-Nonafluoro-butane-1-sulfonic acid9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yl ester

To a suspension of9-benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(4.0 g, 11.4 mmol) in dichloromethane (250 ml) was added pyridine (8.9mL, 114 mmol). The reaction mixture was stirred at ambient temperaturefor 10 min then cooled to 0° C. and nonafluorobutanesulfonic anhydride(7.01 mL, 22.9 mmol) added over 10 minutes. The mixture was allowed towarm to ambient temperature and stirred for 2.5 h. After this time, thereaction was cooled to 0° C., aqueous hydrochloric acid (1M, 120 mL) wasadded and the resulting mixture extracted with dichloromethane (3×100mL). The combined organic phase was dried over sodium sulfate, filteredand concentrated in vacuo. The resultant residue was purified by flashchromatography (silica, 50 g column, Si-SPE, DCM) to afford the titlecompound as a pale yellow solid (5.34 g, 74%). ¹H NMR (CDCl₃, 300 MHz):9.93 (s, 1H), 8.84 (dd, J=4.8, 1.65 Hz, 1H), 8.67 (dd, J=8.1, 1.65 Hz,1H), 8.33-8.28 (m, 2H), 7.71-7.63 (m, 1H), 7.59-7.51 (m, 3H).

Step 3:9-Benzenesulfonyl-5-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of 1,1,2,2,3,3,4,4,4-nonafluoro-butane-1-sulfonic acid9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yl ester(5.43 g, 8.4 mmol) and tetrabutylammonium bromide (10.0 g, 31 mmol) in1,4-dioxane (175 mL) was heated at 100° C. for 30 min. The reactionmixture was allowed to cool to ambient temperature then evaporated invacuo to afford the title compound as a white solid (2.38 g, 68%). ¹HNMR (DMSO-D₆, 300 MHz): 9.74 (s, 1H), 9.02 (dd, J=8.1, 1.6 Hz, 1H), 8.84(dd, J=4.8, 1.6 Hz, 1H), 8.29-8.22 (m, 2H), 7.78-7.68 (m, 2H), 7.67-7.58(m, 2H).

Step 4:9-Benzenesulfonyl-5-(1-ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of 1-ethyl-4-methylene-piperidine (540 mg, 4.32 mmol) and9-borabicyclo[3.3.1]nonane (0.5M in THF, 8.0 mL, 4.0 mmol) was heated at65° C. for 3.5 h. The resultant cooled solution was then addedportionwise to a degassed suspension of9-benzenesulfonyl-5-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(420 mg, 1 mmol), bis(diphenylphosphino)ferrocene dichloropalladium(II)(90 mg, 0.11 mmol) and potassium carbonate (180 mg, 1.3 mmol) in water(1 mL) and dimethylformamide (10 mL). The resultant orange solution washeated at 65° C. for 2 h then allowed to cool to ambient temperature andpartitioned between dichloromethane (20 mL) and a saturated aqueoussolution of sodium chloride (15 mL). The aqueous phase was extractedwith dichloromethane (3×10 mL) and the combined organic phase was washedwith a saturated aqueous solution of sodium chloride (20 mL), dried overmagnesium sulfate and concentrated in vacuo. The resultant residue waspurified by flash chromatography (silica, 10 g column, Si-SPE, 0-20%MeOH in DCM) to afford the title compound (200 mg, 43%). ¹H NMR (CDCl₃,400 MHz): 9.81 (s, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.66 (d, J=8.0 Hz,1H), 8.29-8.24 (m, 2H), 7.66-7.60 (m, 1H), 7.58-7.48 (m, 3H), 3.41 (d,J=7.2 Hz, 2H), 2.89 (q, J=7.3 Hz, 2H), 2.56-2.44 (m, 2H), 2.33-2.08 (m,3H), 1.94-1.74 (m, 4H), 1.35 (t, J=7.3 Hz, 3H). LCMS (Method G):R_(T)=3.01 min, M+H⁺=460.

Step 5:5-(1-Ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of9-benzenesulfonyl-5-(1-ethyl-piperidin-4-ylmethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(200 mg, 0.4 mmol) and triethylamine (4 mL) in methanol (40 mL) wasstirred at ambient temperature for 6 days. The mixture was concentratedin vacuo and the residue purified by flash chromatography (silica, 2 gcolumn, Si-SPE, 0-20% MeOH in DCM). The resultant material wastriturated with acetonitrile and methanol to afford the title compoundas a white solid (65 mg, 51%). NMR (DMSO-D₆, 400 MHz): 12.85 (s, 1H),8.90 (s, 1H), 8.70 (dd, J=4.8, 1.5 Hz, 1H), 8.65 (dd, J=8.0, 1.6 Hz,1H), 7.46 (dd, J=8.0, 4.8 Hz, 1H), 2.86-2.77 (m, 2H), 2.24 (q, J=7.2 Hz,2H), 1.84-1.58 (m, 5H), 1.54-1.40 (m, 2H), 0.95 (t, J=7.1 Hz, 3H). LCMS(Method H): R_(T)=4.56 min, M+H⁺=320.

Example 3266-Cyano-5-(1-ethylpiperidin-4-yloxy)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-3-carboxylicacid methyl ester

9-Benzenesulfonyl-3-bromo-5-(1-ethylpiperidin-4-yloxy)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile(150 mg, 0.278 mmol), molybdenum hexacarbonyl (73 mg, 0.278 mmol),Herman's catalyst(trans-di(μ-acetato)bis[(2-di-o-tolylphosphino)benzyl]dipalladium(II),26 mg, 0.028 mmol) and tri-tert-butylphosphonium tetrafluoroborate (20mg, 0.069 mmol) were placed in a 5 mL microwave vial. Dioxane (3 mL),methanol (1.5 mL) followed by 1,8-diazabicyclo(5.4.0)undec-7-ene (0.12mL, 0.833 mmol) were added to the mixture, the tube sealed and heatedunder microwave irradiation at 150° C. for 15 min. The cooled reactionmixture was diluted with water and extracted into ethyl acetate (4×50mL). The combined organic phase was washed with brine, dried over sodiumsulfate and concentrated in vacuo to afford a residue that was purifiedby flash chromatography (silica, 12 g column, ISCO, 0-10% MeOH in DCM).The resultant material was triturated with MeOH and collected byfiltration to afford the title compound as a pale yellow powder (29 mg,28%). ¹H NMR (CDCl₃, 300 MHz): 9.35 (d, J=2.1 Hz, 1H), 9.23 (s, 1H),8.83 (s, 1H), 5.21-5.06 (m, 1H), 4.05 (s, 3H), 3.07-2.88 (m, 2H),2.59-2.44 (m, 2H), 2.41-2.06 (m, 6H), 1.20-1.07 (m, 3H). LCMS (MethodH): R_(T)=6.56 min, M+H⁺=380.

Example 3275-(1-Ethylpiperidin-4-yloxy)-3-isopropyl-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile

Step 1:5-(1-Ethylpiperidin-4-yloxy)-3-isopropenyl-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile

9-Benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile(147 mg, 0.272 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.014 mmol) were dissolved inTHF (9 mL) and 1N aqueous sodium carbonate (3 mL) added followed byisopropenylboronic acid pinacol ester (0.076 mL, 0.408 mmol) and placedunder an argon atmosphere. The reaction mixture was heated undermicrowave irradiation at 140° C. for 50 min. The cooled reaction mixturewas diluted with saturated aqueous sodium hydrogen carbonate solution(20 mL) and extracted into ethyl acetate (4×20 mL). The combined organicphase was washed with brine (20 mL), dried over sodium sulfate andconcentrated in vacuo to afford the title compound as a brown solid (163mg) which was used without further purification in the next step. ¹H NMR(CDCl₃, 300 MHz): 12.05 (br s, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (s,1H), 8.64 (d, J=2.2 Hz, 1H), 5.48 (s, 1H), 5.28-5.24 (m, 1H), 5.09-4.97(m, 1H), 3.02-2.91 (m, 2H), 2.49 (q, J=7.2 Hz, 2H), 2.35-2.20 (m, 7H),2.19-2.07 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).

Step 2:5-(1-Ethylpiperidin-4-yloxy)-3-isopropyl-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile

A suspension of5-(1-ethylpiperidin-4-yloxy)-3-isopropenyl-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile(98 mg, 0.271 mmol), 10% palladium on carbon (50 mg) and triethylamine(0.5 mL) in IMS (5 mL) was stirred at ambient temperature under ahydrogen atmosphere for 18 h. The mixture was filtered through a PTFEfilter and the filtrate concentrated in vacuo to give a brown solid. Theresultant solid was purified by flash chromatography (silica, 12 gcolumn, ISCO, 0-5% MeOH in DCM) to afford the title compound as a whitesolid (27 mg, 27%). ¹H NMR (DMSO-D₆, 300 MHz): 12.96 (s, 1H), 8.82 (s,1H), 8.68 (s, 1H), 8.32 (s, 1H), 5.11-4.77 (m, 1H), 3.65-3.48 (m, 2H),3.28-3.18 (m, 2H), 3.14-2.90 (m, 3H), 2.42-2.18 (m, 4H), 1.37 (d, J=6.9Hz, 6H), 1.29-1.17 (m, 3H). LCMS (Method H): R_(T)=7.10 min, M+H⁺=364.

Example 3285-(1-Ethylpiperidin-4-yloxy)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-3,6-dicarbonitrile

DMF (8 mL) was added to a mixture of9-benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile(200 mg, 0.37 mmol), zinc cyanide (217 mg, 1.85 mmol) andtetrakis(triphenylphosphine) palladium(0) (43 mg, 0.04 mmol) and thereaction mixture heated under microwave irradiation at 150° C. for 30min. Triethylamine (2 mL) was then added and the reaction mixture heatedat 50° C. for 24 h. The mixture was diluted with saturated aqueoussodium bicarbonate solution (100 mL) and extracted into 10% MeOH in DCM(2×25 mL). The combined organic phase was adsorbed onto HM-N thenpurified by flash chromatography (silica, 12 g column, ISCO, 0-10% MeOHin DCM) to afford the title compound as a cream solid (6 mg, 5%). ¹H NMR(DMSO-D₆, 400 MHz): 9.07 (d, J=2.0 Hz, 1H), 8.99 (d, J=1.9 Hz, 1H), 8.84(s, 1H), 4.86-4.76 (m, 1H), 2.97-2.87 (m, 2H), 2.42 (q, J=7.2 Hz, 2H),2.23-2.13 (m, 2H), 2.12-1.94 (m, 4H), 1.03 (t, J=7.2 Hz, 3H). LCMS(Method H): R_(T)=5.27 min, m+H⁺=347.

Example 3295-[1-(2,22-Trifluoroethyl)-piperidin-4-ylmethyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:4-(9-Benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester

A mixture of 4-methylene-piperidine-1-carboxylic acid tert-butyl ester(0.70 g, 3.55 mmol) and 9-borabicyclo[3,3,1]nonane (0.5M solution inTHF, 7 mL, 3.5 mmol) were heated at reflux for 1.5 h. The reactionmixture was cooled and added to a degassed mixture of9-benzenesulfonyl-5-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(0.41 g, 1.0 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.090 g, 0.11 mmol) and potassiumcarbonate (0.18 g, 1.3 mmol) in water (1 mL) and DMF (10 mL) and thereaction mixture was then heated at 65° C. for 1.25 h. After cooling toambient temperature the reaction mixture was then diluted with water (5mL) and dichloromethane (10 mL). The aqueous phase was extracted withdichloromethane (2×15 mL) and the combined organic phase was washed withbrine (15 mL), dried over magnesium sulfate, filtered and concentratedin vacuo. The residue was triturated with pentane (10 mL) and theresultant material was purified by flash chromatography (silica, 5 gcolumn, SPE-Si II, 0-2% methanol in DCM) to afford title compound as ayellow solid (202 mg, 38%). NMR (CDCl₃, 400 MHz): 9.81 (s, 1H), 8.79(dd, J=4.8, 1.6 Hz, 1H), 8.33-8.27 (m, 3H), 7.66-7.60 (m, 1H), 7.55-7.46(m, 3H), 4.22-4.01 (m, 2H), 3.34-3.27 (m, 2H), 2.62-2.50 (m, 2H),1.97-1.76 (m, 2H), 1.72-1.46 (m, 3H), 1.45 (s, 9H).

Step 2:9-Benzenesulfonyl-5-piperidin-4-ylmethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A solution of4-(9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-ylmethyl)-piperidine-1-carboxylicacid tert-butyl ester (202 mg, 0.38 mmol) in dichloromethane (6 mL) wastreated with trifluoroacetic acid (2 mL) and the resultant mixturestirred for 1 h then concentrated in vacuo. The residue was purified byflash chromatography (silica, 5 g column, SPE-NH₂, 0-8% methanol in DCM)to give title compound as an off white solid (150 mg, 80%). LCMS (MethodG): R_(T)=3.07 min, M+H⁺=432.

Step 3:9-Benzenesulfonyl-5-[1-(2,2,2-trifluoroethyl)-piperidin-4-ylmethyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

N,N-Diisopropylethylamine (100 mg, 0.77 mmol) and trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (100 mg, 0.43 mmol) in THF (1mL) were added to a solution of9-benzenesulfonyl-5-piperidin-4-ylmethyl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrilein THF (4 mL) and resultant mixture stirred at ambient temperature for30 min. The mixture was then filtered through a 2 g SiII SPE cartridge,eluting with THF. The THF washings were concentrated in vacuo and theresultant residue was purified by flash chromatography (silica, 2 gcolumn, Si II SPE, 0-20% ethyl acetate in DCM) to afford title compoundas a white solid (0.16 g, 85%). ¹H NMR (CDCl₃, 400 MHz): 9.81 (d, J=2.9Hz, 1H), 8.81-8.75 (m, 1H), 8.34 (d, J=8.1 Hz, 1H), 8.28 (d, J=7.9 Hz,2H), 7.66-7.59 (m, 1H), 7.55-7.45 (m, 3H), 3.35-3.27 (m, 2H), 3.02-2.88(m, 5H), 2.32-2.21 (m, 2H), 1.86-1.60 (m, 4H).

Step 4:5-[1-(2,2,2-Trifluoroethyl)-piperidin-4-ylmethyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

9-Benzenesulfonyl-5-[1-(2,2,2-trifluoroethyl)-piperidin-4-ylmethyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(0.16 g, 0.3 mmol) was dissolved in tetrabutylammonium fluoride (1M inTHF, 5 mL, 5 mmol) and stirred at ambient temperature for 24 h. Thesolution was filtered through 2 g NH₂ cartridge, eluting with 1:1methanol/dichloromethane. The filtrate was concentrated in vacuo and theresidue diluted with water (10 mL) and the resultant precipitatecollected by filtration. Purification of the solid by flashchromatography (silica, 5 g column, SPE Si-II, 0-6% methanol in DCM)afforded the title compound as a white solid (90 mg, 80%). ¹H NMR(DMSO-D₆, 400 MHz): 12.88 (s, 1H), 8.91 (s, 1H), 8.72-8.64 (m, 2H), 7.46(dd, J=8.0, 4.8 Hz, 1H), 3.09 (q, J=10.3 Hz, 2H), 2.92-2.83 (m, 2H),2.25-2.15 (m, 2H), 1.85-1.72 (m, 1H), 1.66-1.58 (m, 2H), 1.57-1.43 (m,2H). LCMS (Method H): R_(T)=9.20 min, M+H⁺=374.

Example 3305-(Azetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

Step 1:9-Benzenesulfonyl-5-(1-benzhydrylazetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile

A mixture of9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(210 mg, 0.50 mmol), cesium carbonate (320 mg, 0.98 mmol) and sodiumiodide (37 mg, 0.24 mmol) in DMF (10 mL) were heated at 130° C. for 10minutes. After cooling to ambient temperature the reaction mixture wasthen diluted with water (5 mL) and ethyl acetate(3×10 mL). The combinedorganic phase was washed with brine (15 mL), dried over magnesiumsulfate, filtered and concentrated in vacuo. Purification of the residueby flash chromatography (silica, 12 g column, SPE Si—II, 0-10% methanolin DCM) afforded the title compound as a white solid (240 mg, 76%). LCMS(Method G): R_(T)=4.12 min, M+H⁺=652.

Step 2:5-(Azetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole-6-carbonitrile

To a stirred solution of9-benzenesulfonyl-5-(1-benzhydrylazetidin-3-yloxy)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile(238 mg, 0.37 mmol) in methanol (10 mL) at 0° C. was added a solution of1-chloroethyl chloroformate (120 μL, 1.1 mmol) in DCM (10 mL). Thereaction mixture was allowed to warm to ambient temperature then heatedat 40° C. for 4 h. The reaction was cooled to ambient temperature andthen concentrated in vacuo. Purification of the residue by flashchromatography (silica, 11 g column, SPE NH₂, 0-20% methanol in DCM)afforded the title compound as a white solid (5 mg, 5%). ¹H NMR (CDCl₃plus CD₃OD, 400 MHz): 8.85 (s, 1H), 8.74-8.69 (m, 2H), 8.08 (s, 1H),7.93 (s, 1H), 5.73-5.64 (m, 1H), 4.19-4.05 (m, 4H), 4.01 (s, 3H). LCMS(Method G): R_(T)=5.59 min, M+H⁺=346.

The compounds of the Examples in Table 16 were prepared using themethods described above from commercially available starting materialsand the general Suzuki Methods.

TABLE 16 Suzuki Puri- LCMS Ex- Cou- fication R_(T), am- pling Meth- M +H⁺, ple Structure/Name Method od(s) Method ¹H NMR (ppm) 331

  6-(1-Methyl-1H-pyrazol-4-yl)-3-(4- piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole I B¹ 4.7, 423, A (CD₃OD, 300 MHz): 8.85(d, J = 1.1 Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H),8.31 (d, J = 1.1 Hz, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.69 (d, J = 8.0Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 4.01 (s, 3H), 3.60 (s, 2H), 2.56-2.44(m, 4H), 1.71-1.58 (m, 4H), 1.55-1.45 (m, 2H). 332

  6-(1-Ethyl-1H-pyrazol-4-yl)-3-(4- piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole I C, B, E, D 4.9, 437, A (DMSO-D₆, 400MHz): 12.12 (s, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.90 (d, J = 2.3 Hz, 1H),8.85 (d, J = 1.1 Hz, 1H), 8.51 (d, J = 1.1 Hz, 1H), 8.26 (d, J = 0.7 Hz,1H), 8.00 (d, J = 0.7 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.45 (d, J =7.9 Hz, 2H), 4.21 (q, J = 7.3 Hz, 2H), 3.50 (s, 2H), 2.41- 2.34 (m, 4H),1.58-1.48 (m, 4H), 1.47- 1.37 (m, 5H). 333

  3-(4-Piperidin-1-ylmethyl-phenyl)- 6-(1-propyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole I C, B, D 951, 451, A (DMSO-D₆, 400 MHz):12.13 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.90 (d, J = 2.3 Hz, 1H), 8.86(d, J = 1.1 Hz, 1H), 8.52 (d, J = 1.1 Hz, 1H), 8.25 (d, J = 0.7 Hz, 1H),8.01 (d, J = 0.7 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz,2H), 4.14 (t, J = 6.9 Hz, 2H), 3.49 (s, 2H), 2.40-2.34 (m, 4H),1.91-1.80 (m, 2H), 1.56-1.48 (m, 4H), 1.43-1.38 (m, 2H), 0.88 (t, J =7.4 Hz, 3H). 334

  6-(1-Isobutyl-1H-pyrazol-4-yl)-3-(4- piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole J B 5.5, 465, A (CD₃OD, 300 MHz): 8.85(d, J = 1.0 Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.78 (d, J = 2.2 Hz, 1H),8.32 (d, J = 1.1 Hz, 1H), 8.08 (s, 1H), 8.07 (s, 1H), 7.72 (d, J = 8.0Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 4.02 (d, J = 7.3 Hz, 2H), 3.74 (s,2H), 2.70-2.58 (m, 4H), 2.35-2.19 (m, 1H), 1.73-1.64 (m, 4H), 1.59-1.48(m, 2H), 0.98 (d, J = 6.7 Hz, 6H). 335

  6-(1-Benzyl-1H-pyrazol-4-yl)-3-(4- piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole J N, O, P, Q³ 5.8, 499, A (CD₃OD, 300MHz): 8.84 (d, J = 1.1 Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.77 (d, J =2.2 Hz, 1H), 8.33 (d, J = 1.1 Hz, 1H), 8.13 (d, J = 0.7 Hz, 1H), 8.12(d, J = 0.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H),7.42-7.29 (m, 5H), 5.42 (s, 2H), 3.60 (s, 2H), 2.55- 2.45 (m, 4H),1.68-1.60 (m, 4H), 1.53- 1.47 (m, 2H). 336

  6-(1,5-Dimethyl-1H-pyrazol-4-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H- dipyrido[2,3-b;4′,3′-d]pyrrole J O4.7, 437, A (CD₃OD, 300 MHz): 8.93 (d, J = 1.1 Hz, 1H), 8.81 (d, J = 2.2Hz, 1H), 8.75 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 1.1 Hz, 1H), 7.82 (s,1H), 7.68 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 3.89 (s, 3H),3.59 (s, 2H), 2.60 (s, 3H), 2.52-2.45 (m, 4H), 1.69-1.59 (m, 4H),1.54-1.45 (m, 2H). 337

  3-(4-Piperidin-1-ylmethyl-phenyl)-6- thiazol-5-yl-9H-dipyrido[2,3-b;4′,3′-d]pyrrole 6.02, 426, A (CDCl₃ plus CD₃OD, 300 MHz): 8.93(d, J = 1.1 Hz, 1H), 8.92 (d, J = 0.7 Hz, 1H), 8.85 (d, J = 2.2 Hz, 1H),8.82 (d, J = 2.2 Hz, 1H), 8.56 (d, J = 1.1 Hz, 1H), 8.43 (d, J = 0.7 Hz,1H), 7.75-7.70 (m, 2H), 7.55-7.49 (m, 2H), 3.71 (s, 2H), 2.67- 2.53 (m,4H), 1.74-1.63 (m, 4H), 1.59- 1.47 (m, 2H) plus one exchangeable notobserved.

Example 3383-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1: 5-Bromo-2-fluoro-[3,4′]bipyridinyl-3′-ylamine

A mixture of 4-iodo-pyridin-3-ylamine (1.027 g, 4.67 mmol),2-fluoro-5-bromopyridine-3-boronic acid (2.05 g, 9.33 mmol), and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complexwith dichloromethane (1:1) (191 mg, 0.233 mmol) in acetonitrile (12 mL)and 1N aqueous potassium fluoride solution (12 mL) was heated at 95° C.for 3 h. The reaction mixture was allowed to cool, treated withadditional portions of the boronic acid (0.5 eq) and of catalyst (5.0mol %), and heated under reflux overnight under a nitrogen atmosphere.The mixture was allowed to cool, diluted with DCM and water, andfiltered to remove the solids. The filtrate layers were separated andthe aqueous phase was extracted into DCM, and the combined organic phaseconcentrated in vacuo. The resultant residue was redissolved in 20%methanol in DCM and absorbed onto silica gel for purification by flashchromatography (silica, 100 g column, Biotage, 1-20% methanol in DCM) toafford the title compound as a brown solid (861 mg, 69%). ¹H NMR(DMSO-D₆, 400 MHz): 8.43 (d, J=1.1 Hz, 1H), 8.18 (dd, J=8.3 Hz, 2.5 Hz,1H) 8.11 (s, 1H), 7.81 (d, J=4.8 Hz, 1H), 7.01 (d, J=4.8 Hz, 1H), 5.37(s, 2H). LCMS (Method B): R_(T)=0.95 min, M+H⁺=268/270.

Step 2:5-(4-Piperidin-1-ylmethyl-phenyl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine

A degassed mixture of 5-bromo-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (861mg, 3.21 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (816 mg, 3.72mmol) and bis(triphenylphosphine)palladium(II) chloride (169 mg, 0.241mmol) in acetonitrile (14 mL) and 1N aqueous potassium fluoride solution(8.0 mL) was heated under microwave irradiation at 100° C. for 25minutes. The cooled reaction mixture was diluted with water and 20%methanol in DCM, the layers separated, and the aqueous phase extractedinto 20% methanol in DCM. The combined organic phase was concentrated invacuo, and the resultant residue dissolved in DCM/methanol, absorbedonto celite, and purified by flash chromatography (silica, 100 g column,Biotage, 0-20% methanol in DCM) to afford the title compound as a darkorange foam (753 mg, 65%). ¹H NMR (DMSO-D₆, 400 MHz): 8.58 (s, 1H), 8.20(d, J=7.1 Hz, 1H), 8.13 (s, 1H), 7.84 (d, J=4.8 Hz, 1H), 7.74 (m, 2H),7.43 (m, 2H), 7.07 (d, J=4.9 Hz, 1H), 5.31 (s, 2H), 3.29 (s, 2H), 2.35(m, 4H), 1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method B): R_(T)=1.27 min,M+H⁺=363.

Step 3:3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A 1N solution of bis(trimethylsilyl)amide in THF (2.78 mL, 2.80 mmol)was added dropwise to a solution of5-(4-piperidin-1-ylmethyl-phenyl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine(101 mg, 0.278 mmol) in THF (5.0 mL) at ambient temperature. The mixturewas stirred for 1 h at ambient temperature and then treated with water.The resultant brown solution was partitioned between DCM and water, thelayers separated, and the aqueous phase extracted into 20% methanol inDCM. The combined organic phase was concentrated in vacuo. The resultantresidue was absorbed onto silica gel, and purified by flashchromatography (silica, 1-20% methanol in DCM) to provide a lightorange-yellow solid (39.9 mg, 42%). ¹H NMR (DMSO-D₆, 500 MHz): 12.24 (s,1H), 8.99 (d, J=1.8 Hz, 1H), 8.93 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.45(d, J=5.2 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.77 (d, J=7.5 Hz, 2H), 7.45(d, J=7.5 Hz, 2H), 3.49 (s, 2H), 2.36 (m, 4H), 1.52 (m 4H), 1.41 (m,2H). LCMS (Method D): R_(T)=4.64 min, M+H⁺=343.

Example 3393-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid

A degassed mixture of3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid (37.7 mg,0.13 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid, pinacol ester(58.5 mg, 0.194 mmol) and bis(triphenylphosphine)palladium(II)dichloride (4.5 mg, 6.4 μmol) in acetonitrile (2 mL) and aqueous sodiumcarbonate solution (2 mL) was heated under microwave irradiation at 140°C. for 10 minutes. The cooled reaction mixture was acidified with 10%aqueous sulfuric acid, filtered, and the crude solution was purified bypreparative HPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the titlecompound. ¹H NMR (DMSO-D₆, 400 MHz): 12.62 (s, 1H), 9.66 (s, 1H),9.14-8.95 (m, 4H), 7.77 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 3.97(d, J=13.4 Hz, 2H), 3.55 (d, J=11.6 Hz, 2H), 3.20 (q, J=11.1 Hz, 2H),3.04 (t, J=11.9 Hz, 2H), 2.89 (s, 3H). LCMS (Method D): R_(T)=5.09 min,M+H⁺=388.

Example 3403-(1-Methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid

A degassed mixture of3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester(30.4 mg, 99.3 μmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(31.0 mg, 0.149 mmol), and bis(triphenylphosphine)palladium(II)dichloride (3.5 mg, 5.0 μmol) in acetonitrile (2.5 mL) and 2N aqueoussodium carbonate solution (2.5 mL) was heated under under microwaveirradiation at 140° C. for 10 minutes. The cooled reaction mixture wasacidified with 10% aqueous sulfuric acid, the solid removed byfiltration and the resultant filtrate purified by preparative HPLC(0-30% MeCN over 30 min, 35 mL/min) to afford the title compound. ¹H NMR(DMSO-D₆, 500 MHz): 12.84 (s, 1H), 9.04 (d, J=2.1 Hz, 1H), 8.95 (s, 2H),8.91 (d, J=2.1 Hz, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 6.48 (s, 1H), 3.92(s, 3H). LCMS (Method D): R_(T)=5.24 min, M+H⁺=294.

Example 3413-(3-Trifluoromethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid

A degassed mixture of3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid (20.0 mg,68.5 μmol), 3-(trifluoromethyl)phenylboronic acid (19.5 mg, 0.103 mmol),and bis(triphenylphosphine)palladium(II) dichloride (2.4 mg, 3.4 μmol)in acetonitrile (0.3 mL) and 2N aqueous sodium carbonate solution (0.3mL) was heated under microwave irradiation at 140° C. for 10 minutes.The cooled reaction mixture was acidified with 10% aqueous sulfuricacid. The solid was removed by filtration and the resultant filtrate waspurified by preparative HPLC (5-45% MeCN over 45 min, 35 mL/min) toafford the title compound. ¹H NMR (DMSO-D₆, 400 MHz): 12.75 (s, 1H),9.38-9.00 (m, 3H), 8.21 (m, 1H), 7.78 (m, 2H), 7.65-7.60 (m, 2H). LCMS(Method D): R₁=10.76 min, M+H⁺=358.

Example 3423-(3-{N-[(4-Methoxyphenyl)methyl]aminocarbonyl}phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid

Step 1: 3-{N-[(4-Methoxyphenyl)methyl]aminocarbonyl} phenylboronic acid

3-Carboxyphenylboronic acid (140 mg, 0.84 mmol), PyBOP (376 mg, 0.72mmol) and HOBt (97.7 mg, 0.72 mmol) were dissolved in DMF (3.18 mL) andtreated with DIPEA (420 μL, 2.41 mmol). After 5 min at ambienttemperature, 4-methoxybenzenemethanamine (78 μL, 0.60 mmol) was added.The homogeneous reaction mixture was stirred at ambient temperature for16 h, the solvent was removed under reduced pressure, and the residuepurified by preparative HPLC (5-40% MeCN over 40 min, 35 mL/min) toafford the product as a white solid.

Step 2:3-(3-{N-[(4-Methoxyphenyl)methyl]aminocarbonyl}phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid

A degassed mixture of3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester(40.4 mg, 0.13 mmol),N-[(4-methoxyphenyl)methyl]aminocarbonyl}phenylboronic acid (41.4 mg,0.15 mmol) and bis(triphenylphosphine)palladium(II) dichloride (4.6 mg,66 mmol) in acetonitrile (3.3 mL) and 2N aqueous sodium carbonatesolution (3.3 mL) was heated under microwave irradiation at 140° C. for10 minutes. The cooled reaction mixture was acidified with 10% aqueoussulfuric acid. The solid was removed by filtration, and the resultantfiltrate was purified by preparative HPLC (5-40% MeCN over 40 min, 35mL/min) to afford the title compound. ¹H NMR (DMSO-D₆, 400 MHz): 12.74(s, 1H), 9.28 (m, 1H), 9.13 (m, 1H), 9.07 (m, 1H), 9.00 (m, 1H), 8.35(m, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.65 (t, J=7.7Hz, 1H), 7.30 (q, J=8.6 Hz, 2H), 6.91 (q, J=8.6 Hz, 2H), 4.48 (d, J=5.8Hz, 2H), 3.73 (s, 3H). LCMS (Method D): R_(T)=9.61 min, M+H⁺=423.

Example 3433-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxamide

A solution of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid methyl ester (67.3 mg, 0.168 mmol) in 7M ammonia in methanol (8.0mL) was heated to 70° C. for 24 h in a sealed tube. The mixture wasallowed to cool and concentrated in vacuo. The residue was dissolved inDMSO and purified by preparative HPLC (2-60% MeCN/water modified with0.1% ammonium hydroxide) to afford a light-yellow fluffy solid (10.3 mg,16%). ¹H NMR (DMSO-D₆, 500 MHz): 12.56 (s, 1H), 9.18 (d, J=2.2 Hz, 1H),9.00 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.90 (s, 1H), 8.10 (s, 1H), 7.79(d, J=8.1 Hz, 2H), 7.53 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 3.49 (s, 2H),2.36 (m, 4H), 1.56-1.47 (m, 4H), 1.40 (m, 2H). LCMS (Method D):R_(T)=5.88 min, M+H⁺=386.

Example 344N-Ethyl-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxamide

A solution of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid methyl ester (152 mg, 0.380 mmol) in 2-Methylamine in THF (8.0 mL)was heated to 80° C. for 4 days in a sealed tube. The mixture wasallowed to cool and concentrated in vacuo. The residue was redissolvedin DMSO and purified by preparative HPLC [2-60% MeCN/water modified with0.1% ammonium hydroxide] to afford a dark brown solid (74.9 mg, 48%). ¹HNMR (DMSO-D₆, 500 MHz): 9.19 (d, J=2.2 Hz, 1H), 8.99 (s, 1H), 8.97 (d,J=2.2 Hz, 1H), 8.91 (s, 1H), 8.72 (m, 1H), 8.24 (s, 1H), 7.81 (d, J=8.1Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.47-3.33 (m, 2H), 2.38 (m, 4H), 1.53(m, 4H), 1.42 (m, 2H), 1.18 (t, J=7.2 Hz, 3H). LCMS (Method E):R_(T)=3.30 min, M+H⁺=414.

Example 345N-(2-Aminoethyl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxamide

A solution of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid methyl ester (152 mg, 0.380 mmol) in ethylenediamine (8.0 mL) washeated to 80° C. for 16 h in a sealed tube. The mixture was allowed tocool and concentrated in vacuo. The residue was dissolved in DMSO andpurified by preparative HPLC (2-60% MeCN/water modified with 0.1%ammonium hydroxide) to afford a light brown solid (45.4 mg, 28%). ¹H NMR(DMSO-D₆, 400 MHz): 9.19 (d, J=2.1 Hz, 1H), 8.99 (s, 1H), 8.96 (d, J=2.2Hz, 1H), 8.92 (s, 1H), 8.74 (m, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.45 (d,J=8.1 Hz, 2H), 3.50 (s, 2H), 3.41-3.33 (m, 2H), 2.76 (t, J=6.4 Hz, 2H),2.38 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): R_(T)=6.45min, M+H⁺=429.

Example 3463-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid amide

DIPEA (14 μL, 77 μmol) was added to a solution of3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid (20.0 mg, 51.6 μmol), PyBOP (28.2 mg, 54.2 μmol) and HOBt (8.4 mg,62 μmol) in DMF (1 mL). After 10 min at ambient temperature, a solutionof 0.5M ammonia in 1,4-dioxane (500 μL, 0.258 mmol) was added to thereaction mixture. After 30 min the reaction mixture was acidified with10% aqueous sulfuric acid and made homogeneous with the addition ofDMSO. The crude solution was purified by preparative HPLC (0-30% MeCNover 30 min, 35 mL/min) to afford the title compound. ¹H NMR (DMSO-D₆,400 MHz): 12.48 (s, 1H), 9.11-8.89 (m, 4H), 7.77 (d, J=8.9 Hz, 2H), 7.18(d, J=8.9 Hz, 2H), 3.97 (d, J=13.5 Hz, 2H), 3.55 (q, J=12.2 Hz, 2H),3.20 (q, J=11.4 Hz, 2H), 3.03 (t, J=12.0 Hz, 2H), 2.89 (s, 3H). LCMS(Method D): R_(T)=6.35 min, M+H⁺=387.

Example 3473-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid dimethylamide

DIPEA (14 μL, 77 μmol) was added to a solution of3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid (20.0 mg, 51.6 mop, PyBOP (28.2 mg, 54.2 mop and HOBt (8.4 mg, 62μmol) in DMF (0.6 mL). After 10 min at ambient temperature,dimethylamine hydrochloride (20.0 mg, 0.258 mmol) and DIPEA (45 μL, 0.26mmol) were added to the reaction mixture. After 30 min the reactionmixture was acidified with 10% aqueous sulfuric acid, the solid removedby filtration and the resultant filtrate was purified by preparativeHPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the title compound.¹H NMR (DMSO-D₆, 400 MHz): 12.40 (s, 1H), 9.03 (m, 1H), 8.92 (m, 1H),8.89 (m, 1H), 8.55 (m, 1H), 7.75 (d, J=8.9 Hz, 2H), 7.18 (d, J=8.9 Hz,2H), 3.97 (d, J=12.2 Hz, 2H), 3.56 (d, J=12.2 Hz, 2H), 3.21 (m, 2H),3.08 (m, 6H), 3.02 (m, 2H), 2.98 (s, 3H). LCMS (Method D): R_(T)=6.19min, M+H⁺=415.

Example 3483-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid (2-hydroxy-ethyl)amide

DIPEA (13.5 μL, 77.4 μmol) was added to a solution of3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid (20.0 mg, 51.6 μmol), PyBOP (28.2 mg, 54.2 μmol) and HOBt (8.4 mg,62 μmol) in DMF (0.6 mL). After 10 min at ambient temperature,ethanolamine (16 μL, 0.26 mmol) was added to the reaction mixture. After30 min the resultant mixture was acidified with 10% aqueous sulfuricacid and concentrated in vacuo. The resultant residue was dissolved inDMF, water and 10% aqueous sulfuric acid and purified by preparativeHPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the title compound.¹H NMR (DMSO-D₆, 400 MHz): 12.49 (s, 1H), 9.71 (br.s, 1H), 9.14 (d,J=2.1 Hz, 1H), 8.90 (s, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.66 (t, J=5.8 Hz,1H), 7.77 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 3.97 (d, J=13.4 Hz,2H), 3.57 (m, 4H), 3.45 (m, 2H), 3.20 (m, 2H), 3.04 (m, 2H), 2.89 (s.3H), LCMS (Method D): R_(T)=6.31 min, M+H⁺=431.

Example 3496-(Pyrrolidinylcarbonyl)-3-[4-(4-methylpiperizin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6-(Pyrrolidinylcarbonyl)-3-bromo-9H-dipyrido[2,3-b:4′,3′-d]pyrrole

3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester(140 mg, 0.458 mmol) was dissolved in pyrrolidine (6 mL) and the mixtureheated to reflux for 2 h. The mixture was allowed to cool andconcentrated in vacuo to afford a bright orange oily solid. The residuewas used without purification.

Step 2:6-(Pyrrolidinylcarbonyl)-3-[4-(4-methylpiperizin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-(pyrrolidinylcarbonyl)-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (158mg, 0.457 mmol), 4-(4-methylpiperizin-1-yl)-phenyl-1-boronic acid,pinacol ester (597 mg, 1.98 mmol), andbis(triphenylphosphine)palladium(II) chloride (69.0 mg, 99.0 μmol, 5.0mol %) in acetonitrile (2.5 mL) and 1.0M aqueous sodium carbonate (2.5mL) was heated under microwave irradiation at 120° C. for 10 minutes,allowed to cool, and partitioned between ethyl acetate and water. Theorganic layer was dried over sodium sulfate filtered and concentrated invacuo. The resultant residue was purified by preparative HPLC (0-30%MeCN/water modified with 0.1% formic acid) to afford an off-white solid(10.0 mg, 5%). ¹H NMR (DMSO-D₅, 400 MHz) 12.39-12.29 (s, 1H), 9.01 (d,J=2.2 Hz, 1H), 8.88 (d, J=2.2 Hz, 31), 8.86 (s, 1H), 8.70 (s, 1H), 7.69(d, J=8.7 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 3.78 (t, J=6.2 Hz, 2H), 3.57(t, J=6.2 Hz, 2H), 3.25-3.18 (m, 4H), 2.47 (m, 3H), 2.24 (m, 4H), 1.87(m, 4H). LCMS (Method D): R_(T)=7.36 min, M+H⁺=441.

Example 3503-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-methanol

A 1M solution of lithium aluminum hydride in THF (1.2 mL, 1.2 mmol) wasslowly added to a suspension of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid methyl ester (48.0 mg, 0.120 mmol) in THF at 0° C. The mixture wasslowly warmed to ambient temperature. A further portion of 1M solutionof lithium aluminum hydride in THF (1.2 mL, 1.2 mmol) was added slowlyto the bright orange-yellow, homogeneous mixture at ambient temperature.After 1 h, the mixture was treated with aqueous ammonium chloride, anddiluted with water and 50% DCM/methanol. The resulting mixture wastreated with Rochelle's salt and allowed to stir vigorously for 2 h. Thesolids were removed by filtration, and the filtrate layers wereseparated. The aqueous phase was extracted with 20% methanol in DCM andthe combined organic phase concentrated in vacuo. The residue wasdissolved in DMSO and purified by preparative HPLC (2-60% MeCN/watermodified with 0.1% ammonium hydroxide) to provide a light-yellow solid(7.1 mg, 16%). ¹H NMR (DMSO-D₆, 400 MHz): 12.10 (s, 1H), 9.02 (m, 1H),8.90 (m, 1H), 8.82 (m, 1H), 8.28 (m, 1H), 7.79 (m, 2H), 7.46 (m, 2H),5.40 (t, J=5.7 Hz, 1H), 4.74 (d, J=5.6 Hz, 2H), 3.59-3.41 (m, 2H), 2.38(m, 4H), 1.54 (m, 414), 1.42 (m, 2H). LCMS (Method D): R_(T)=4.48 min,M+H⁺=373.

Example 351{3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-methanol

Step 1: 3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-methanol

Lithium aluminium hydride (1M solution in THF, 16.3 mL, 16.3 mmol) wasadded dropwise to a suspension of3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester(500 mg, 1.63 mmol) in THF (10 mL). After 10 minutes the reactionmixture was quenched with a solution of saturated ammonium chloride,diluted with DCM and water and the solid removed by filtration. Thelayers of the resultant filtrate were separated and the aqueous phasewas further extracted with DCM. The combined organic layer wasconcentrated in vacuo and purified by flash chromatography (silica,1-15% methanol in DCM).

Step 2:{3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-methanol

A suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-methanol(40.7 mg, 0.146 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acidpinacol ester (46.4 mg, 0.154 mmol) andbis(triphenylphosphine)palladium(II) dichloride (5.1 mg, 7.3 mmol) inacetonitrile (0.73 mL) and 2N aqueous sodium carbonate solution (0.73mL) was heated at 150° C. under microwave irradiation for 20 minutes.The cooled reaction mixture was diluted with THF, the solid removed byfiltration, and washed with THF and DCM. The combined filtrate wasconcentrated in vacuo and the resultant residue purified by flashchromatography (silica, 1-15% (2N ammonia methanol) in DCM) to affordthe title compound. ¹H NMR (DMSO-D₆, 400 MHz): 12.46 (s, 1H), 9.76 (s,1H), 9.07 (d, J=1.8 Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 7.76(d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H), 4.13 (s, 2H), 3.38-3.30 (m,8H), 2.89 (s, 3H). LCMS (Method D): R_(T)=5.24 min, M+H⁺=374.

Example 3522-{3-[4-(4-Methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-propan-2-ol

Step 1:3-[4-(4-Methyl-piperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid methyl ester

3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester(100 mg, 0.327 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid,pinacol ester (104 mg, 0.343 mmol) andbis(triphenylphosphine)palladium(II) dichloride (11.5 mg, 0.016 mmol)were suspended in acetonitrile (1.8 mL) and 1N aqueous potassium acetatesolution (1.8 mL) and heated under microwave irradiation at 140° C. for30 minutes. The cooled reaction mixture was diluted with saturatedsodium bicarbonate solution and DCM, and the solid removed byfiltration. The layers of the resultant filtrate were separated and theaqueous phase was further extracted with DCM. The combined organic phasewas dried over sodium sulfate, filtered and concentrated in vacuo. Theresultant residue was purified by flash chromatography (silica, 0-20%(MeOH containing 1% triethylamine) in DCM).

Step 2:2-{3-[4-(4-Methyl-piperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-propan-2-ol

A solution of 3N methylmagnesium chloride in THF (545 μL, 1.6 mmol) wasadded to a suspension of3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid methyl ester (54.7 mg, 0.136 mmol) in THF (4 mL) at ambienttemperature. After 5 minutes the reaction mixture was quenched withsaturated ammonium chloride solution and diluted with DCM and water. Thelayers were separated and the aqueous phase was further extracted withDCM. The combined organic phase was dried over sodium sulfate, filtered,and concentrated in vacuo. The resultant residue was dissolved in water,DMF, and 10% aqueous sulfuric acid and purified by preparative HPLC(0-30% MeCN over 40 min, 35 mL/min) to afford the title compound. ¹H NMR(DMSO-D₆,400 MHz): 12.85 (s, 1H), 9.78 (s, 1H), 9.15-8.84 (m, 4H), 7.78(d, J=8.7 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 3.98 (d, J=13.6 Hz, 2H), 3.60(m, 2H), 3.20 (q, J=10.0 Hz, 2H), 3.03 (t, J=12.4 Hz, 2H), 2.89 (s, 3H),1.65 (s, 6H). LCMS (Method D): R_(T)=2.91 min, M+H⁺=402.

Example 3536-Bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Method 1: Step 1:6′-Bromo-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine

A mixture of 6-bromo-4-iodopyridin-3-amine (3.3 g, 8.0 mmol),2-fluoro-3-boronic acid-5-(4-piperidin-1-ylmethylphenyl)pyridine (3.2 g,10.0 mmol), and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (360 mg,0.44 mmol) in 1N aqueous potassium fluoride (21 mL) and acetonitrile (45mL) was heated at 90° C. for 4 h. The cooled reaction was diluted withwater (100 mL) and extracted with DCM (3×50 mL). The combined organiclayer was dried over sodium sulfate, filtered, and evaporated to afforda residue which was purified by flash chromotagraphy (silica, 25 gcolumn, Biotage, 0-10% methanol in (DCM containing 1% 2M ammonia inmethanol)) to afford the title compound as a yellow/orange solid (3.2 g,91%). ¹H NMR (DMSO-D₆, 500 MHz,): 8.62 (s, 1H), 8.25 (d, J=7.3 Hz, 1H),7.90 (s, 1H), 7.74 (d, J=6.5 Hz, 2H), 7.42 (d, J=6.5 Hz), 7.35 (s, 1H),5.57 (s, 2H), 3.47 (s, 2H), 2.34 (s, 4H), 1.51 (s, 4H), 1.40 (s, 2H).

Step 2:6-Bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

To a solution of 6′-bromo-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (1.5 g,3.4 mmol) in anhydrous tetrahydrofuran (41 mL) was added sodiumbis(trimethylsilyl)amide (1N solution in THF, 10.5 mL, 10 mmol) under aflow of nitrogen. The reaction mixture was left to stir at roomtemperature for 1 h then quenched by the addition of acetic acid (1 mL).The reaction mixture was evaporated in vacuo to afford a residue thatwas purified by flash chromotagraphy (silica, 25 g column, Biotage,0-10% methanol in (DCM containing 1% 2M ammonia in methanol) to affordthe title compound as an off-white solid (620 mg, 43%). ¹H NMR (DMSO-D₆,400 MHz) 12.37 (s, 1H), 9.03 (d, J=2.5 Hz, 1H), 8.95 (d, J=2.5 Hz, 1H),8.71 (s, 1H), 8.52 (s, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz,2H), 3.51 (s, 2H), 2.38 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS(Method D): R_(T)=8.63 min, M+H⁺=422/424.

Method 2: Step 1:6′-Chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine

A degassed mixture of5-bromo-6′-chloro-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (1.35 g, 4.46mmol), 4-(piperidin-1-ylmethyl)phenylboronic acid hydrobromide (2.28 g,7.59 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.29 g,0.35 mmol) in acetonitrile (70 mL) and 1N aqueous potassium fluoridesolution (12 mL) was heated under microwave irradiation at 100° C. for30 minutes. The cooled reaction was diluted with water (100 mL) andextracted with DCM (3×50 mL). The combined organic layer was dried oversodium sulfate, filtered, and evaporated to afford a residue which waspurified by flash chromotagraphy (silica, 25 g column, Biotage, 0-10%methanol in (DCM containing 1% 2M ammonia in methanol)) to afford thetitle compound as a yellow/orange solid (0.95 g, 54%).

Step 2:6-Bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

To a solution of6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine(1.6 g, 0.004 mol) in 1,4-dioxane (30 mL) was added bromotrimethylsilane(27 mL, 0.2 mol) which immediately produced a white precipitate. Thereaction was heated at 100° C. for 48 h. The solid from the cooledreaction mixture was collected by filtration and washed with ethylacetate (2×20 mL). The resultant solid was then purified by flashchromotagraphy (silica, 25 g column, Biotage, 0-10% methanol in (DCMcontaining 1% 2M ammonia in methanol)) to afford the title compound asan off-white solid (1.1 g, 45%). ¹H NMR (DMSO-D₆, 500 MHz,): 8.62 (s,1H), 8.25 (d, J=7.3 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=6.5 Hz, 2H), 7.42(d, J=6.5 Hz), 7.35 (s, 1H), 5.57 (s, 2H), 3.47 (s, 2H), 2.34 (s, 4H),1.51 (s, 4H), 1.40 (s, 2H).

Example 3546-Chloro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of 3-bromo-6-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(1.00 g, 3.55 mmol),1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidinehydrochloride (1.24 g, 3.67 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloro palladium(II) (0.29 g, 0.35 mmol) in acetonitrile (20mL) and 2N aqueous potassium fluoride solution (10 mL) was heated undermicrowave irradiation at 140° C. for 30 minutes. The cooled reactionmixture was concentrated under reduced pressure and taken up inDCM/methanol and loaded onto an SCX-2 cartridge (20 g) which was thenwashed with methanol (50 mL) then 2N ammonia in methanol (50 mL). Thecombined basic fractions were concentrated in vacuo and the residuepurified by flash chromatography (silica, 80 g column, ISCO, 0-10%methanol in DCM) to afford the title compound as a pink solid (0.87 g,66%). ¹H NMR (DMSO-D₆, 400 MHz): 12.38 (s, 1H), 9.03 (d, J=2.3 Hz, 1H),8.95 (d, J=2.3 Hz, 1H), 8.71 (d, J=1.0 Hz, 1H), 8.38 (d, J=0.9 Hz, 1H),7.75 (d, J=7.9 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 3.49 (s, 2H), 2.39-2.33(m, 4H), 1.56-1.48 (m, 4H), 1.45-1.37 (m, 2H). LCMS (Method B):R_(T)=2.27 min, M+H⁺=377.

Example 3556-Chloro-3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of 3-bromo-6-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(43.0 mg, 0.152 mmol), 4-(4-methylpiperizin-1-yl)-phenyl-1-boronic acid,pinacol ester (48.2 mg, 0.159 mmol) andbis(triphenylphosphine)palladium(II) chloride (5.3 mg, 7.6 μmol, 5.0 mol%) in acetonitrile (0.63 mL) and 1M aqueous potassium acetate (0.63 mL)was heated under microwave irradiation at 140° C. for 30 minutes,allowed to cool and concentrated in vacuo. The residue was dissolved inwater, DMF, and 10% sulfuric acid and purified by preparative HPLC(0-30% MeCN/water modified with 0.1% formic acid) to afford a lightyellow solid (21.3 mg, 35%). ¹H NMR (DMSO-D₆, 400 MHz): 12.34 (s, 1H),8.96 (d, J=2.2 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.70 (s, 1H), 8.38 (s,1H), 7.66 (d, J=8.7, 3H), 7.09 (d, J=8.8, 3H), 3.26-3.17 (m, 4H), 2.47(m, 4H), 2.24 (s, 3H). LCMS (Method D): R_(T)=8.90 min, M+H⁺=378.

Example 3566-Chloro-3-(1-methylpyrazol-4-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of 3-bromo-6-chloro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(34.6 mg, 0.122 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(26.8 mg, 0.129 mmol), and bis(triphenylphosphine)palladium(II) chloride(4.3 mg, 6.1 μmol, 5.0 mol %) in acetonitrile (0.51 mL) and 1M aqueouspotassium acetate (0.51 mL) was heated under microwave irradiation at140° C. for 30 minutes, allowed to cool and concentrated in vacuo. Theresidue was dissolved in water, DMF, and 10% sulfuric acid and purifiedby preparative HPLC (0-30% MeCN/water modified with 0.1% formic acid) toafford an off-white solid (15.4 mg, 44%). ¹H NMR (DMSO-D₆, 400 MHz):12.32 (s, 1H), 8.89 (s, 2H), 8.69 (d, J=0.7 Hz, 1H), 8.28 (d, J=0.7 Hz,1H), 8.22 (s, 1H), 7.96 (s, 1H), 3.90 (s, 3H). LCMS (Method D):R_(T)=9.61 min, M+H⁺=284.

Example 3576-Fluoro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1: 6-Fluoro-4-iodopyridin-3-ylamine

(6-Fluoro-4-iodopyridin-3-yl)-carbamic acid tert-butyl ester (1.75 g,5.18 mmol) was dissolved in DCM (25 mL) and TFA (5 mL) added. Themixture was stirred at ambient temperature for 1 h and then evaporatedin vacuo. The resultant residue was treated with saturated aqueoussodium hydrogen carbonate solution (25 mL), diluted with water (100 mL)and extracted into ethyl acetate (2×100 mL). The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated in vacuoto afford the title compound as an orange oil, which crystallized onstanding (1.23 g, 99%). ¹H NMR (CDCl₃, 300 MHz): 7.61 (d, J=1.6 Hz, 1H),7.28-7.25 (m, 1H), 3.99 (s, 2H). LCMS (Method B): R_(T)=2.52 min,M+H⁺=239.

Step 2: 5-Bromo-2,6′-difluoro-[3,4′]bipyridinyl-3′-ylamine

A mixture of 6-fluoro-4-iodopyridin-3-ylamine (1.57 g, 6.59 mmol),2-fluoro-5-bromopyridine-3-boronic acid (2.17 g, 9.89 mmol) and1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.43 g,0.53 mmol) in acetonitrile (25 mL) and 1N aqueous potassium fluoridesolution (25 mL) was degassed with nitrogen for 20 minutes. The reactionmixture was heated at 80° C. for 3 h, allowed to cool to ambienttemperature and then partitioned between ethyl acetate (100 mL) andwater (75 mL). The organic layer was separated, dried over sodiumsulfate, filtered and evaporated in vacuo. The resultant residue waspurified by flash chromatography (silica, 40 g column, ISCO, 0-50% ethylacetate in cyclohexane) to afford the title compound as an brown solid(0.54 g, 29%). ¹H NMR (CDCl₃, 300 MHz): 8.37 (dd, J=2.5, 1.4 Hz, 1H),7.99 (dd, J=8.1, 2.5 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 6.74 (d, J=2.8 Hz,1H), 3.62 (s, 2H). LCMS (Method B): R_(T)=3.01 min, M+H⁺=286/288.

Step 3: 3-Bromo-6-fluoro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of 5-bromo-2,6′-difluoro-[3,4′]bipyridinyl-3′-ylamine (0.79g, 2.76 mmol) in THF (15 mL) was added dropwise over 10 minutes tosodium bis(trimethylsilyl)amide (1N solution in THF, 5.5 mL, 5.52 mmol).The reaction mixture was left to stir for 20 minutes then quenched bythe addition of water (2 mL). The resultant black solution waspartitioned between ethyl acetate (75 mL) and water (50 mL) and thelayers separated. The organic phase was dried over sodium sulfate,filtered and evaporated in vacuo to give an off white solid. Theresultant solid was triturated with ethyl acetate (30 mL), collected byfiltration, washed with diethyl ether (5 mL) and left to air dry toafford the title compound as an off white solid (0.51 g, 65%), ¹H NMR(DMSO-D₆, 300 MHz): 9.00 (d, J=2.3 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H), 8.51(dd, J=1.7, 0.9 Hz, 1H), 7.95 (dd, J=2.4, 0.9 Hz, 1H). LCMS (Method B):R_(T)=3.10 min, M+H⁺=266/268.

Step 4:6-Fluoro-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of 3-bromo-6-fluoro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (100 mg,0.38 mmol), 4-benzylpiperidine boronic acid (123 mg, 0.56 mmol) and1,1′-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (31 mg,0.038 mmol) in acetonitrile (1.5 mL) and 2N aqueous potassium fluoridesolution (1.5 mL) was degassed with nitrogen for 20 minutes. Thereaction mixture was then heated under microwave irradiation at 150° C.for 30 minutes, allowed to cool to ambient temperature and diluted withwater (3 mL). The resultant precipitate was collected by filtration,washed with water (5 mL) and ethyl acetate (10 mL). The resultant solidresidue was purified by flash chromatography (silica, 4 g column, ISCO,0-20% methanol in DCM) to afford the title compound as an off whitesolid (90 mg, 67%). ¹H NMR (DMSO-D₆, 300 MHz): 12.27 (s, 1H), 9.00 (d,J=2.3 Hz, 1H), 8.93 (d, J=2.3 Hz, 1H), 8.49 (d, J=1.5 Hz, 1H), 7.98 (d,J=2.3 Hz, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.43 (d, J=7.9 Hz, 2H), 3.48 (s,2H), 2.42-2.29 (m, 4H), 1.54-1.47 (m, 4H), 1.44-1.34 (m, 2H). LCMS(Method A): R_(T)=5.87 min, M+H⁺=361.

Example 3586-oxo-3-(4-piperidin-1-ylmethyl-phenyl)-6,7-dihydro-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

To6-methoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(200 mg, 0.5 mmol) was added HBr (33% in acetic acid, 5 mL) and thereaction was heated at 100° C. for 16 h. The cooled reaction mixture wasthen evaporated in vacuo to afford a residue that was purified bypreparative HPLC [0-30% MeCN in water (0.1% formic acid) over 30 min, 35mL/min] to afford the title compound as a bright yellow solid (50 mg,30%). ¹H NMR (DMSO-D₆, 400 MHz): 11.51 (s, 1H), 8.91-8.74 (m, 2H), 8.28(s, 1H), 7.72 (d, J=8.2 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.29 (s, 1H),6.68-6.44 (s, 1H), 3.48 (s, 2H), 2.36 (s, 4H), 1.51 (m, 4H), 1.40 (m,2H). LCMS (Method D): R_(T)=4.97 min, M+H⁺=359.

Example 3596-Methoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1: tert-Butyl 6-methoxypyridin-3-ylcarbamate

A mixture of 6-methoxypyridin-3-amine (14 g, 0.11 mol) anddi-tert-butyldicarbonate (32 g, 0.15 mol) in 1,4-dioxane (100 mL) washeated at 75° C. for 16 h. The cooled reaction mixture was diluted withethyl acetate (200 mL) and washed with water (150 mL). The organic phasewas separated, dried over sodium sulfate, filtered and evaporated invacuo to afford a residue that was purified by flash chromotagraphy(silica, 120 g column, ISCO, 0-40% ethyl acetate in hexanes) to affordthe title compound as a pink solid (20 g, 80%).

Step 2: (6-Methoxy-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester

n-Butyllithium (2.5M in hexanes, 100 mL, 240 mmol) was added dropwiseover 1 h to a cooled (−78° C.) mixture oftert-butyl-6-methoxypyridin-3-ylcarbamate (16 g, 71 mmol) andN,N,N′,N′-tetramethylethylenediamine (34 mL, 221 mmol) in diethyl ether(100 mL). The reaction was stirred at −78° C. for 30 minutes, thenwarmed to −20° C. and left stirring for 3 h. The reaction mixture wastransferred via cannula over fifteen minutes to a cold (−78° C.)solution of 1-chloro-2-iodoethane (48 g, 243 mmol) in diethyl ether (50mL). On complete addition, the reaction mixture was allowed to warm toroom temperature and left stirring at this temperature for 16 h. Thereaction was quenched with saturated aqueous ammonium chloride (30 mL)and water (200 mL) then extracted with ethyl acetate (2×100 mL). Thecombined organic layer was washed with saturated sodium sulfite (50 mL),1N hydrochloric acid (100 mL), water (100 mL), saturated sodiumbicarbonate solution (100 mL) and brine (50 mL), dried over sodiumsulfate, and evaporated to give a residue which was purified by flashchromatography (silica, 120 g column, ISCO, 0-40% ethyl acetate inhexanes) to afford the title compound as a white cyrstaline solid (18 g,72%).

Step 3: 6-Methoxy-4-iodopyridin-3-amine

A solution of (6-methoxy-4-iodo-pyridin-3-yl)-carbamic acid tert-butylester (18 g, 51 mmol) in DCM (50 mL) and TFA (50 mL) was stirred atambient temperature for 1 h and then evaporated in vacuo. The resultantresidue was treated with saturated aqueous sodium hydrogen carbonatesolution (25 mL), diluted with water (100 mL) and extracted into ethylacetate (2×100 mL). The organic layer was separated, dried over sodiumsulfate, filtered and evaporated in vacuo to afford the title compoundas a brown foam (10 g, 60%).

Step 4: 5-Bromo-6′-methoxy-2-fluoro-[3,4′]bipyridinyl-3′-ylamine

A mixture of 6-methoxy-4-iodopyridin-3-amine (9.5 g, 38 mmol),5-bromo-2-fluoropyridin-3-ylboronic acid (16.7 g, 76 mmol), and1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.5 g, 2mmol) in 1N aqueous potassium fluoride (95 mL) and acetonitrile (200 mL)was heated at 95° C. for 16 h. The cooled reaction mixture was dilutedwith water (100 mL) and extracted with DCM (3×100 mL). The combinedorganic layer was dried over sodium sulfate, filtered, and evaporated toafford a residue which was purified by flash chromotagraphy (silica, 120g column, ISCO, 0-40% ethyl acetate in hexanes) to afford the titlecompound as a yellow/orange solid (8.0 g, 71%).

Step 5:6′-Methoxy-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine

A mixture of 6′-methoxy-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (1.0 g,3.4 mmol), 4-(piperidin-1-ylmethyl)phenylboronic acid hydrobromide (1.7g, 5.7 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.18g, 0.25 mmol) in 1N aqueous potassium fluoride (8.4 mL) and acetonitrile(12 mL) was heated under microwave irradiation at 100° C. for 25minutes. The cooled reaction was diluted with water (100 mL) andextracted with DCM (3×50 mL). The combined organic layer was, dried oversodium sulfate, filtered, and purified by flash chromotagraphy (silica,25 g column, Biotage, 0-10% methanol in (DCM containing 1% 2M ammonia inmethanol)) to afford the title compound as a yellow/orange solid (1.0 g,77%). ¹H NMR (DMSO-D₆, 500 MHz): 8.59 (s, 1H), 8.22 (d, J=8.0 Hz, 1H),7.74 (s, 3H), 7.42 (s, 2H), 6.65 (s, 1H), 4.71 (s, 2H), 3.77 (s, 3H),3.47 (s, 2H), 2.34 (s, 4H), 1.51 (s, 4H), 1.40 (s, 2H).

Step 6:6-Methoxy-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

To a solution of 6′-methoxy-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (43mg, 0.11 mmol) in anhydrous tetrahydrofuran (1.8 mL) was added sodiumbis(trimethylsilyl)amide (1N solution in THF, 0.33 mL, 0.332 mmol) undera flow of nitrogen. The reaction was left to stir at room temperaturefor 1 h then quenched with acetic acid (1 mL). The reaction mixture wasevaporated in vacuo to afford a residue that was purified by preparativeHPLC [0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min] toafford the title compound as a beige solid (10 mg, 20%). ¹H NMR(DMSO-D₆, 400 MHz): 11.82 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.85 (d,J=2.3 Hz, 1H), 8.47 (s, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.64 (s, 1H), 7.42(d, J=8.2 Hz, 2H), 3.92 (s, 3H), 3.48 (s, 2H), 2.36 (s, 4H), 1.51 (m,4H), 1.40 (m, 2H). LCMS (Method E): R_(T)=2.40, M+H⁺=373.

Example 3606-Methoxy-3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1: 6-Methoxy-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A 1N solution of bis(trimethylsilyl)amide in THF (6.81 mL, 6.81 mmol)was added dropwise to a solution of5-bromo-2-fluoro-6′-methoxy-[3,4]bipyridinyl-3′-ylamine (203 mg, 0.681mmol) in THF (12.0 mL). The reaction mixture was stirred for 30 minutesat ambient temperature, diluted with water, and extracted into ethylacetate. The organic phase was dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude residue was dissolved in ethyl acetateand methanol, absorbed onto silica gel, and purified by flashchromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate inhexanes) to provide the title compound as an orange-tan solid (89.0 mg,47%). ¹H NMR (DMSO-D₆, 400 MHz): 12.44-12.12 (m, 1H), 7.79 (d, J=2.6 Hz,1H), 7.66 (d, J=3.5 Hz, 2H), 6.56 (s, 1H), 3.75 (s, 3H). LCMS (MethodB): R_(T)=1.83 min, M+H⁺=278/280.

Step 2:6-Methoxy-3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-methoxy-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (89.0 mg, 0.320mmol), 4-(4-methylpiperazin-1-yl)-phenyl-1-boronic acid, pinacol ester(102 mg, 0.336 mmol) and bis(triphenylphosphine)palladium(II) chloride(11.2 mg, 16.0 umol, 5.0 mol %) in acetonitrile (1.3 mL) and 1M aqueouspotassium acetate (1.3 mL) was heated under microwave irradiation at140° C. for 30 minutes, allowed to cool to room temperature andconcentrated. The residue was dissolved in water, DMF, and 10% sulfuricacid and purified by preparative HPLC [0-25% MeCN/water modified with0.1% formic acid] to afford a light yellow solid (17.3 mg, 15%). NMR(DMSO-D₆, 500 MHz): 11.72 (s, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.80 (d,J=2.3 Hz, 1H), 8.46 (m, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.63 (s, 1H), 7.09(d, J=8.8 Hz, 2H), 3.92 (s, 3H), 3.28 (s, 3H), 2.71 (m, 4H), 2.41 (m,4H). LCMS (Method D): R_(T)=6.70 min, M+H⁺=374.

Example 3613,6-Bis(1-methyl-4-pyrazolyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1: 3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acidhydrazide

A solution of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid methyl ester (582 mg, 1.90 mmol) and hydrazine hydrate (2.29 mL,47.0 mmol) in ethanol (4.6 mL) was heated under reflux in an inertatmosphere. After 1 h, the reaction mixture was allowed to cool toambient temperature. The resultant precipitate was collected byfiltration, washed with ethanol, and left to air-dry to afford the titlecompound as a tan-yellow solid.

Step 2: 3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acidazide

Hydrogen chloride (3.0 mL, 90 mmol) was added dropwise to a suspensionof 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid hydrazide(530 mg, 1.73 mmol) in water (12.4 mL). Once homogeneous, the solutionwas cooled to 0° C. and a solution of 3N sodium nitrite in water (0.60mL, 2.0 mmol) was added to the mixture. After 1 h, added another 1.03eq. of 3N sodium nitrite in water (0.60 mL, 2.0 mmol) and allowed thereaction to warm to ambient temperature over night. After 17 h at roomtemperature, the reaction was cooled to 0° C. and a solution of 3Nsodium nitrite in water (0.60 mL, 2.0 mmol) was added and then warmed toroom temperature. The reaction was made basic with a solution ofsaturated sodium bicarbonate, and the solid precipitate was collected byfiltration, washed with water, and dried in a dessicator under vacuum toprovide a solid material that was 70% pure by LCMS analysis.

Step 3: 6-Amino-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid azide (1.09 g, 3.44 mmol) in a mixture of 1:1 water-acetic acid(3.52 mL) was heated under reflux for 1 h. The reaction was allowed tocool to ambient temperature and the mixture concentrated in vacuo. Theresultant residue was purified by flash chromatography (silica, 1-20%(MeOH containing 1% of 2N ammonia in MeOH) in DCM) and recrystallizedfrom pyridine to afford the title compound.

Step 4: 3,6-Dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of hydrogen bromide (33%) in acetic acid (1.10 mL, 6.08 mmol)was added to 6-amino-3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (80.1 mg,0.304 mmol) at 0° C. To the resulting suspension was added bromine (18μL, 0.34 mmol), and then a 1N solution of sodium nitrite in water (0.43mL, 0.43 mmol), and the mixture was allowed to warm to ambienttemperature. After 1 h, the reaction mixture was diluted withconcentrated ammonium hydroxide-water (1:1) and DCM, filtered to removethe solid, and the filtrate layers separated. The aqueous phase wasextracted into DCM and the combined organic phase was concentrated invacuo. The residue was purified by flash chromatography (silica, 0-100%ethyl acetate in hexanes).

Step 5: 3,6-Bis(1-Methyl-4-pyrazolyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A suspension of 3,6-dibromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (9.3 mg,28 μmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(17.8 mg, 85.3 μmol) and bis(triphenylphosphine)palladium(II) dichloride(1.0 mg, 14 mop in acetonitrile (0.18 mL) and 2N aqueous sodiumcarbonate solution was heated under microwave irradiation at 140° C. for20 minutes. The reaction mixture was allowed to cool to ambienttemperature and the resultant precipitate collected by filtration, andthe solid washed sequentially with water, DCM, and 20% MeOH in DCM. Thefiltrate was combined, the layers separated, and the aqueous phaseextracted into 20% MeOH in DCM. The combined organic phase wasconcentrated in vacuo and the resultant residue purified by flashchromatography (silica, 0-20% MeOH in DCM) to afford the title compound.¹H NMR (DMSO-D₆, 400 MHz): 12.01 (s, 1H), 8.83 (m, 2H), 8.78 (m, 1H),8.39 (s, 1H), 8.21 (d, J=9.4 Hz, 2H), 7.97 (d, J=7.0 Hz, 2H), 3.98-3.91(s, 6H). LCMS (Method D): R_(T)=7.53 min, M+H⁺=330.

Example 3623-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-amine

Step 1:tert-Butyl-{3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-carbamate

A suspension of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonylazide (50.0 mg, 0.158 mmol) in toluene (3.0 mL) was treated withtert-butyl alcohol (1.00 mL, 10.4 mmol) and heated under reflux for 1 hunder a nitrogen atmosphere. The solution was allowed to cool to ambienttemperature and the resulting precipitate was collected by filtration,washed with DCM, and dried under vacuum to afford an orange solid (55.9mg, 98%). The solid was used without purification. ¹H NMR (DMSO-D₆, 400MHz): 12.12 (s, 1H), 9.57 (s, 1H), 8.99 (d, J=2.2 Hz, 1H), 8.62 (d, J=2Hz2, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 1.51 (s, 9H).

Step 2:tert-Butyl-{3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-carbamate

A degassed mixture oftert-butyl-{3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-carbamate(229 mg, 0.631 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (207mg, 0.946 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (51.5 mg, 6.31 μmol, 10.0 mol %) in 1,4-dioxane(12.4 mL) and 2M aqueous cesium carbonate (1.32 mL) was heated underreflux for 5 h. The mixture was allowed to cool to room temperature,diluted with DCM and water, and filtered to remove the precipitate. Thefiltrate layers were separated and the aqueous phase was extracted withDCM, and the combined organic phase concentrated in vacuo. The resultantresidue was dissolved in 20% methanol in DCM and absorbed onto silicagel for purification by flash chromatography (silica, 11 g column,Biotage, 1-20% methanol in DCM) to afford the title compound as a beigesolid (86.9 mg, 30%). ¹H NMR (DMSO-D₆, 400 MHz): 11.96 (s, 1H), 9.55 (s,1H), 8.99 (d, J=1.9 Hz, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.57 (d, J=7.8 Hz,2H), 7.80 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.35(m, 4H), 1.55-1.45 (m, 4H), 1.52 (s, 9H), 1.39 (m, 2H). LCMS (Method D):R_(T)=9.11 min, M+H⁺=458.

Step 3:3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-amine

A degassed mixture oftert-butyl-{3-Bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-carbamate(105 mg, 0.290 mmol), 4-piperidin-1-ylmethyl-phenyl boronic acid (73.7mg, 0.336 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (17.8 mg, 2.18 μmol, 7.5 mol %) in acetonitrile(1.3 mL) and 1M aqueous potassium acetate (1.3 mL) was heated undermicrowave irradiation at 140° C. for 30 minutes. The cooled reactionmixture was diluted with 20% MeOH in DCM and water, and filtered toremove the solids. The filtrate layers were separated and the aqueousphase was extracted into 20% MeOH in DCM, and the combined organic phaseconcentrated in vacuo. The resultant residue was purified by preparativeHPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) toafford the title compound as a yellow solid (41 mg, 40%). ¹H NMR(DMSO-D₆, 400 MHz): 11.47 (s, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.73 (d,J=2.0 Hz, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.41(d, J=8.1 Hz, 2H), 7.18 (s, 1H), 3.48 (s, 2H), 2.38 (m, 4H), 1.57-1.47(m, 4H), 1.41 (m, 2H). LCMS (Method D): R_(T)=6.20 min, M+H⁺=358.

Example 363N-{3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl-methanesulfonamide

A solution of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine(82.1 mg, 0.230 mmol) in pyridine (8.2 mL) was treated withmethanesulfonyl chloride (58.7 μL, 0.758 mmol) and heated at 50° C. for15 h. The cooled reaction mixture was treated with saturated sodiumbicarbonate solution and diluted with 20% MeOH in DCM and water. Thelayers were separated, the aqueous phase extracted into 20% MeOH in DCM,and the combined organic phases were dried over sodium sulfate andconcentrated in vacuo. The resultant residue was purified by preparativeHPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) toafford the title compound as a tan solid (38 mg, 38%). ¹H NMR (DMSO-D₆,400 MHz): 12.03 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.88 (d, J=2.1 Hz, 1H),8.64 (s, 1H), 7.85 (s, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz,2H), 3.48 (s, 2H), 3.22 (s, 3H), 2.36 (m, 4H), 1.55-1.46 (m, 4H), 1.41(m, 2H). LCMS (Method D): R_(T)=7.37 min, M+H⁺=436.

Example 3641-Ethyl-3-{3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′.,3′-d]pyrrol-6-yl}-urea

A suspension of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine(91.6 mg, 0.256 mmol) in DCM (9.1 mL) was treated with pyridine (22.8μL, 0.282 mmol) and ethylisocyanate (33.2 μL, 0.423 mmol) and then thereaction mixture was heated under reflux for 5 h. The cooled reactionmixture was treated with saturated sodium bicarbonate and diluted with20% MeOH in DCM and water. The layers were separated, the aqueous phaseextracted into 20% MeOH in DCM, and the combined organic phases weredried over sodium sulfate and concentrated in vacuo. The resultantresidue was purified by preparative HPLC (0-30% MeCN in water (0.1%formic acid) over 30 min, 35 mL/min) to afford the title compound as ayellow solid (34 mg, 31%). ¹H NMR (DMSO-D₆, 400 MHz): 9.66 (t, J=5.4 Hz,1H), 9.19 (s, 1H), 8.96 (d, J=2.1 Hz, 1H), 8.91 (d, J=2.1 Hz, 1H), 7.80(d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.20 (s, 1H), 3.53-3.44 (m,4H), 2.36 (m, 4H), 1.58-1.46 (m, 4H), 1.41 (m, 2H), 1.31-1.21 (m, 3H).LCMS (Method D): R_(T)=8.06 min, M+H⁺=429.

Example 365N-{3-(4-Piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl}-isobutyramide

A suspension of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine(80.9 mg, 0.226 mmol) in DCM (1.8 mL) was treated with isobutyrylchloride (26.3 μL, 0.249 mmol) and DIPEA (118 μL, 0.679 mmol). Thereaction mixture was treated with saturated sodium bicarbonate anddiluted with 20% MeOH in DCM and water. The layers were separated, theaqueous phase extracted into 20% MeOH in DCM, and the combined organicphase was dried over sodium sulfate and concentrated in vacuo. Theresultant residue was dissolved in DCM/methanol, absorbed onto celite,and purified by preparative HPLC (0-30% MeCN/water modified with 0.1%formic acid) to afford an off-white solid (12 mg, 12%). ¹H NMR (DMSO-D₆,400 MHz): 12.03 (s, 1H), 10.32 (s, 1H), 8.95 (d, J=2.2 Hz, 1H),8.90-8.85 (m, 2H), 8.62 (s, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1Hz, 2H), 3.48 (s, 2H), 2.79 (dt, J=6.7, 13.5 Hz, 1H), 2.36 (m, 4H),1.58-1.46 (m, 4H), 1.41 (m, 2H), 1.14 (d, J=6.8 Hz, 6H). LCMS (MethodD): R_(T)=7.73 min, M+H⁺=428.

Example 3663-(4-Piperidin-1-ylmethyl-phenyl)-6-(1H-imidazol-1-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine(101.1 mg, 0.283 mmol), paraformaldehyde (9.65 μL, 0.283 mmol), glyoxal(13.0 μL, 0.283 mmol) and 0.17M aqueous ammonium chloride (5.0 mL) in1,4-dioxane (8.4 mL) and water (8.4 mL) was heated at 100° C. for 18 h.The cooled reaction mixture was treated with saturated sodiumbicarbonate and diluted with 20% MeOH in DCM and water. The layers wereseparated, the aqueous phase extracted into 20% MeOH in DCM, and thecombined organic phase was dried over sodium sulfate and concentrated invacuo. The resultant residue was purified by preparative HPLC (0-30%MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) to afford thetitle compound as a white solid (20 mg, 17%). ¹H NMR (DMSO-D₆, 400 MHz):12.37 (s, 1H), 8.96 (s, 2H), 8.82 (s, 1H), 8.67 (s, 1H). 8.49 (s, 1H),7.94 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.16 (s,1H), 3.50 (s, 2H), 2.37 (m, 4H), 1.58-1.46 (m, 4H), 1.41 (m, 2H). LCMS(Method D): R_(T)=6.62 min, M+H⁺=409

Example 3673-(4-piperidin-1-ylmethyl-phenyl)-6-(4H-1,2,4-triazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine(22.3 mg, 62.4 μmol), 1,2-diformylhydrazine (16.5 mg, 0.187 mmol),chloro-trimethylsilane (119 μL, 0.936 mmol) in triethylamine (60.9 μL,0.437 mmol) and pyridine (340 μL) was heated under reflux for 30minutes. The cooled reaction mixture was diluted with water, DCM,methanol and water. The layers were separated; the aqueous phaseextracted with 20% MeOH in DCM, and the combined organic phase wasconcentrated in vacuo. The resultant residue was purified by preparativeHPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) toafford the title compound as a yellow solid (21 mg, 81%). ¹H NMR(DMSO-D₆, 400 MHz): 12.50 (s, 1H), 9.25 (s, 2H), 8.99 (d, J=2.1 Hz, 1H),8.94 (d, J=2.2 Hz, 1H), 8.86 (s, 1H), 8.73 (s, 1H), 7.76 (d, J=8.1 Hz,2H), 7.46 (d, J=8.1 HZ, 2H), 3.50 (s, 2H), 2.35 (m, 4H), 1.58-1.46 (m,4H), 1.41 (m, 2H). LCMS (Method D): R_(T)=7.46 min, M+H⁺=410.

Example 3686-(1-Methyl-1H-1,2,3-triazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6-Iodo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(250 mg, 0.6 mmol), copper (I) iodide (23 mg, 0.12 mmol),N,N′-dimethyl-1,2-ethanediamine (0.013 mL, 0.12 mmol), and sodium iodide(360 mg, 2.4 mmol) in 1,4-dioxane was heated at 110° C. for 3 days. Thereaction was diluted with dichloromethane (20 mL), filtered, andconcentrated to afford a residue that was purified by flashchromatography (silica, 10 g column, Biotage, 0-10% methanol in (DCMcontaining 1% 2M ammonia in methanol)) to afford the title compound asan orange solid (280 mg, 100%).

Step 2:6-(1-Methyl-1H-1,2,3-triazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-iodo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(100 mg, 0.21 mmol), 1-methyl-5-(trimethylstannyl)-1H-1,2,3-triazole(158 mg, 0.64 mmol) and bis(triphenylphosphine)palladium(II) dichloride(15 mg, 0.021 mmol) in N,N-diisopropylethylamine (0.74 mL, 0.43 mmol) in1,4-dioxane (1.7 mL) was heated at 100° C. for 1 h. The cooled reactionmixture was diluted with DCM (20 mL) and methanol (2 mL) and washed withwater (15 mL). The organic phase was separated, dried over sodiumsulfate, filtered and evaporated in vacuo to afford a residue that waspurified by preparative HPLC (20-60% MeCN in water (0.1% ammoniumhydroxide) over 30 min, 35 mL/min) to afford the title compound as apale yellow solid (20 mg, 20%). ¹H NMR (DMSO-D₆, 400 MHz): 12.47 (s,1H), 9.05 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.78(s, 1H), 8.18 (s, 1H), 7.77 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H),4.37 (s, 3H), 3.50 (s, 2H), 2.35 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H).LCMS (method D): R_(T)=8.04 min, M+H⁺=424.

Example 3696-((5-1H-1,2,3-Triazol-4-yl)methanol)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6-(1-Benzyl-4-((tert-butyldimethylsilyloxy)methyl)-1H-1,2,3-triazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to Example368 using1-benzyl-4-((tert-butyldimethylsilyloxy)methyl)-5-(trimethylstannyl)-1H-1,2,3-triazole.The crude reaction mixture was purified by flash chromotagraphy (silica,10 g column, Biotage, 0-10% methanol in DCM containing 1% 7M ammonia inmethanol) to afford a residue that was used in the next step withoutfurther purification.

Step 2:6-((5-1H-1,2,3-Triazol-4-yl)methanol)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of 6-(1-benzyl-4-((tert-butyldimethylsilyloxy)methyl)-1H-1,2,3-triazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrolein 48% aqueous hydrobromic acid (1.5 mL) was heated at 110° C. in asealed tube for 7 h. The cooled reaction mixture was then neutralized bydropwise addition of 6N sodium hydroxide solution. The solvent wasevaporated to afford a residue that was dissolved in DMF and purified bypreparative HPLC (20-60% MeCN in water (0.1% ammonium hydroxide) over 30min, 35 mL/min) to afford the title compound as a pale yellow solid (20mg, 20%). ¹H NMR (DMSO-D₆, 400 MHz): 12.29 (s, 1H), 9.13 (d, J=2.1 Hz,1H), 8.97 (s, 1H), 8.95-8.91 (m, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.44 (d,J=8.1 Hz, 2H), 6.00 (s, 1H), 4.90 (s, 2H), 3.49 (s, 2H), 2.35 (m, 4H),1.52 (m, 4H), 1.41 (m, 2H). LCMS (method D): R_(T)=6.83 min, M+H⁺=440.

Example 3703-(5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6′-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4′]bipyridinyl-3′-ylamine

A degassed mixture of5-bromo-6′-chloro-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (2.0 g, 6.60mmol), bis(pinacolato)diborane (1.84 g, 7.30 mmol),1,1′-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (270 mg,0.33 mmol) and potassium acetate (1.94 g, 19.8 mmol) in dioxane (20 mL)and DMSO (2 mL) was heated under microwave irradiation at 150° C. for 30minutes. The cooled reaction mixture was diluted with ethyl acetate (50mL) the solid removed by filtration and the filtrate was washed withwater (75 mL). The organic phase was dried over sodium sulfate, filteredand evaporated in vacuo to afford a residue that was purified by flashchromatography (silica, 40 g column, ISCO, 0-50% ethyl acetate in DCM)to afford the title compound as a white solid (737 mg, 32%). ¹H NMR(CDCl₃, 300 MHz): 8.67 (dd, J=2.0, 0.8 Hz, 1H), 8.18 (dd, J=10.0, 2.0Hz, 1H), 7.97 (d, J=0.5 Hz, 1H), 7.10 (s, 1H), 1.36 (s, 12H).

Step 2:6′-Chloro-5-(5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine

A degassed mixture of6′-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4′]bipyridinyl-3′-ylamine(1.99 g, 5.70 mmol),2-bromo-5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (1.54 g, 6.30mmol), 1,1′-[bis(diphenylphosphino) ferrocene]dichloropalladium(II) (466mg, 0.57 mmol) in 1N aqueous potassium fluoride solution (22.5 mL) andacetonitrile (22.5 mL) was heated under microwave irradiation at 100° C.for 30 minutes. The cooled reaction mixture was loaded onto an SCX-2cartridge (50 g) and eluted with 2N ammonia in methanol to afford impureproduct as a brown solid. The resultant brown residue was purified byflash chromatography (silica, 40 g column, ISCO, 0-10% methanol in DCM)to afford the title compound as an off-white solid (1.05 g, 47%). ¹H NMR(DMSO-D₆, 300 MHz): 8.48 (d, J=2.4 Hz, 1H), 8.12 (dd, J=9.0, 2.6 Hz,1H), 7.89 (s, 1H), 7.36 (s, 1H), 7.21 (s, 1H), 5.54 (s, 2H), 3.45 (s,2H), 2.86-2.79 (m, 2H), 2.75-2.68 (m, 2H), 2.58-2.51 (m, 2H), 1.08 (t,J=7.1 Hz, 3H).

Step 3:5-(5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-fluoro-6′-(1-methyl-1H-pyrazol-4-yl)-[3,4′]bipyridinyl-3′-ylamine

A degassed mixture of 6′-chloro-5-(5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (1.05g, 2.70 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(842 mg, 4.10 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (221 mg,0.27 mmol) in 1N aqueous potassium fluoride solution (9 mL) andacetonitrile (9 mL) was heated under microwave irradiation at 120° C.for 20 minutes. The cooled reaction mixture was diluted with ethylacetate (100 mL) then washed with water (75 mL). The organic phase wasdried over sodium sulfate, filtered and evaporated in vacuo to afford aresidue that was purified by flash chromatography (silica, 40 g column,ISCO, 0-10% methanol in DCM) to afford the title compound as a whitesolid (641 mg, 55%). NMR (CDCl₃ plus CD₃OD, 300 MHz): 8.44 (dd, J=2.5,1.1 Hz, 1H), 8.13 (d, J=0.6 Hz, 1H), 8.07 (dd, J=8.7, 2.5 Hz, 1H), 7.89(s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.32 (s, 1H), 7.12 (s, 1H), 3.94 (s,3H), 3.61 (s, 2H), 3.00-2.94 (m, 2H), 2.93-2.85 (m, 2H), 2.68 (q, J=7.2Hz, 2H), 1.21 (t, J=7.2 Hz, 3H).

Step 4:3-(5-Ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of sodium bis(trimethylsilyl)amide (1N solution in THF, 4.5mL, 4.5 mmol) was added dropwise over 10 minutes to a solution of5-(5-ethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)-2-fluoro-6′-(1-methyl-1H-pyrazol-4-yl)-[3,4′]bipyridinyl-3′-ylamine(638 mg, 1.50 mmol) in anhydrous THF (26 mL). After 30 minutes, thereaction was quenched by the addition of aqueous saturated aqueouspotassium fluoride solution (10 mL). The resultant brown solution waspartitioned between DCM (75 mL) and brine (50 mL). The organic phase wasseparated, dried over sodium sulfate, filtered and evaporated in vacuoto afford a residue that was purified by flash chromatography (silica,50 g column, Biotage, 0-15% methanol in DCM) to afford the titlecompound as a white solid (96 mg, 16%). ¹H NMR (CDCl₃ plus CD₃OD, 300MHz): 8.82 (s, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.29(s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.11 (s, 1H), 4.00 (s, 3H), 3.64(s, 2H), 3.02-2.95 (m, 2H), 2.93-2.86 (m, 2H), 2.70 (q, J=7.2 Hz, 2H),1.24 (t, J=7.2 Hz, 3H).

Example 3713-(3,5-Dimethoxy-4-piperidin-1-ylmethylphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6′-Chloro-5-(3,5-dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine

A degassed mixture of6′-chloro-2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-[3,4]bipyridinyl-3′-ylamine(630 mg, 1.80 mmol), trifluoromethanesulfonic acid3,5-dimethoxy-4-piperidin-1-ylmethylphenyl ester (1.06 g, 1.98 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (147 mg,0.18 mmol) in 1N aqueous potassium fluoride solution (10 mL) andacetonitrile (8 mL) was heated under microwave irradiation at 100° C.for 30 minutes. The cooled reaction mixture was partitioned between DCM(50 mL) and brine (50 mL). The organic phase was separated, dried oversodium sulfate, filtered and evaporated in vacuo to afford a residuethat was purified by flash chromatography (silica, 20 g column, ISCO,0-10% methanol in DCM) to afford the title compound as a white solid(830 mg, 76%). ¹H NMR (CDCl₃ plus CD₃OD, 300 MHz): 8.52-8.57 (m, 1H),8.12-8.19 (m, 1H), 7.98 (s, 1H), 7.19 (s, 1H), 6.91 (s, 2H), 4.34 (s,2H), 4.01 (s, 6H), 2.87-3.64 (v br m, 4H), 1.63-2.02 (s, 6H).

Step 2:5-(3,5-Dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-6′-(1-methyl-1H-pyrazol-4-yl)-[3,4′]bipyridinyl-3′-ylamine

A degassed mixture of6′-chloro-5-(3,5-dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine(830 mg, 1.40 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(577 mg, 2.78 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (151 mg,0.19 mmol) in 1N aqueous potassium fluoride solution (10 mL) andacetonitrile (6 mL) was heated under microwave irradiation at 100° C.for 20 minutes. The cooled reaction mixture was diluted with ethylacetate (100 mL) then washed with water (75 mL). The organic phase wasseparated, dried over sodium sulfate, filtered and evaporated in vacuoto afford a residue that was purified by flash chromatography (silica,20 g column, ISCO, 0-10% methanol in DCM) to afford the title compoundas a white solid (494 mg, 54%). NMR (CDCl₃ plus CD₃OD, 300 MHz): 8.55(dd, J=2.5, 1.0 Hz, 1H), 8.22 (dd, J=8.8, 2.5 Hz, 1H), 8.16 (d, J=0.6Hz, 1H), 7.92 (s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.37 (s, 1H), 6.95 (s,2H), 4.35 (s, 2H), 4.01 (s, 6H), 3.95 (s, 3H), 3.61-3.22 (br m, 2H),3.19-2.90 (br m, 2H), 2.02-1.47 (br m, 6H).

Step 3:3-(3,5-Dimethoxy-4-piperidin-1-ylmethyl-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of5-(3,5-dimethoxy-4-piperidin-1-ylmethyl-phenyl)-2-fluoro-6′-(1-methyl-1H-pyrazol-4-yl)-[3,4]bipyridinyl-3′-ylamine(490 mg, 0.98 mmol) in anhydrous THF (16.7 mL) was added dropwise over10 minutes to a solution of sodium bis(trimethylsilyl)amide (1N solutionin THF, 2.9 mL, 2.9 mmol). After 30 minutes, the reaction was quenchedby the addition of saturated aqueous potassium fluoride solution (5 mL)and concentrated under reduced pressure to afford a brown residue. Theresultant brown residue was partitioned between ethyl acetate (75 mL)and water (50 mL). The organic phase was separated, dried over sodiumsulfate, filtered and evaporated in vacuo to afford a residue that waspurified by flash chromatography (silica, 50 g column, Biotage, 0-20%methanol in DCM) to afford the title compound as an off-white solid (69mg, 15%). ¹H NMR (CDCl₃ plus CD₃OD, 300 MHz): 8.86 (d, J=1.1 Hz, 1H),8.84-8.80 (m, 2H), 8.37 (d, J=1.1 Hz, 1H), 8.09 (s, 1H), 8.06 (d, J=0.8Hz, 1H), 6.91 (s, 2H), 4.01 (s, 3H), 3.96 (s, 6H), 3.74 (s, 2H),2.64-2.50 (m, 4H), 1.65-1.56 (m, 4H), 1.49-1.37 (m, 2H).

Example 3723-[4-(4,4-Dimethylpiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole

Step 1:6-Bromo-3-[4-(4,4-dimethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of4,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine(836 mg, 2.5 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(500 mg, 1.3 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (109 mg, 0.13 mmol) in 1N aqueous potassiumfluoride solution (25 mL) and acetonitrile (25 mL) was heated at 80° C.for 18 h. The cooled reaction mixture was diluted with ethyl acetate(100 mL) then washed with water (75 mL). The organic phase wasseparated, dried over sodium sulfate, filtered and evaporated in vacuoto afford a residue that was purified by flash chromatography (silica,120 g column, ISCO, 0-15% methanol in DCM) to afford the title compoundas an off-white solid (190 mg, 33%). ¹H NMR (CDCl₃ plus CD₃OD, 300 MHz):8.85 (d, J=2.2 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.70 (d, J=0.9 Hz, 1H),8.32 (d, J=0.9 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H),3.82 (s, 2H), 2.77-2.63 (m, 4H), 1.52 (t, J=5.6 Hz, 4H), 1.00 (s, 6H).

Step 2:3-[4-(4,4-Dimethylpiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-bromo-3-[4-(4,4-dimethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(200 mg, 0.45 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(185 mg, 0.89 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.05 mmol) in 2N aqueous sodium carbonatesolution (5 mL) and acetonitrile (5 mL) was heated under microwaveirradiation at 130° C. for 20 minutes. The cooled reaction mixture wasdiluted with ethyl acetate (100 mL) and washed with water (75 mL). Theorganic phase was separated, dried over sodium sulfate, filtered andevaporated in vacuo to afford a residue that was purified by flashchromatography (silica, 10 g column, Biotage, 0-15% methanol in DCM) toafford the title compound as a white solid (78 mg, 38%). ¹H NMR (CDCl₃plus CD₃OD, 300 MHz): 8.85 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H),8.79 (d, J=2.2 Hz, 1H), 8.33 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 8.06 (d,J=08 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 4.00 (s,3H), 3.63 (s, 2H), 2.51 (t, J=5.0 Hz, 4H), 1.46 (t, J=5.6 Hz, 4H), 0.96(s, 6H).

Example 3733-[4-((2S,6R)-2,6-Dimethyl-piperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole

Step 1:6-Bromo-3-[4-((2S,6R)-2,6-dimethylpiperidin-1-ylmethy)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of(2S,6R)-2,6-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzyl]piperidine(685 mg, 2.08 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(389 mg, 1.04 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (127 mg, 0.16 mmol) in saturated sodium carbonatesolution (1 mL) and THF (10 mL) was heated under reflux for 18 h. Thecooled reaction mixture was diluted with DCM (50 mL) and washed withwater (25 mL). The organic phase was separated, dried over sodiumsulfate, filtered and evaporated in vacuo to afford a residue that waspurified by flash chromatography (silica, 40 g column, ISCO, 0-15%methanol in DCM) to afford the title compound as an off-white solid (181mg, 39%). ¹H NMR (CDCl₃ plus CD₃OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H),8.72 (d, J=2.2 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.29 (d, J=0.9 Hz, 1H),7.68-7.63 (d, J=8.1 Hz, 2H), 7.56-7.50 (m, 2H), 4.00 (s, 2H), 2.65-2.51(m, 2H), 1.72-1.56 (m, 4H), 1.46-1.30 (m, 2H), 1.25 (d, J=6.2 Hz, 6H).

Step 2:3-[4-(2S,6R)-2,6-Dimethylpiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-bromo-3-[4-((2S,6R)-2,6-dimethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(223 mg, 0.50 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(208 mg, 1.0 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (41 mg, 0.05mmol) in 2N aqueous sodium carbonate solution (6 mL) and acetonitrile (6mL) was heated under microwave irradiation at 130° C. for 20 minutes.The cooled reaction mixture was diluted with ethyl acetate (100 mL) andwashed with water (75 mL). The organic phase was separated, dried oversodium sulfate, filtered and evaporated in vacuo to afford a residuethat was purified by flash chromatography (silica, 25 g column, Biotage,0-15% methanol in DCM) to afford the title compound as a white solid (70mg, 31%). NMR (CDCl₃ plus CD₃OD, 300 MHz): 8.85 (d, J=1.1 Hz, 1H),8.82-8.77 (m, 2H), 8.33 (d, J=1.1 Hz, 1H), 8.08 (s, 1H), 8.06 (d, J=0.8Hz, 1H), 7.71-7.65 (m, 2H), 7.56-7.51 (m, 2H), 4.00 (d, J=1.9 Hz, 5H),2.65-2.52 (m, 2H), 1.72-1.60 (m, 3H), 1.47-1.30 (m, 3H), 1.25 (d, J=6.2Hz, 6H).

Example 3746-(1-Methyl-1H-pyrazol-4-yl)-3-(4-morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6-Bromo-3-(4-morpholin-4-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of 4-(4-morpholinomethyl)phenylboronic acid pinacolester (486 mg, 1.61 mmol),3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (400 mg, 1.07 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (131 mg,0.16 mmol) in 2N aqueous sodium carbonate solution (8 mL) and2-methyltetrahyrdofuran (16 mL) was heated at 85° C. for 18 h. Thecooled reaction mixture was diluted with ethyl acetate (100 mL) andwashed with water (75 mL). The organic phase was separated, dried oversodium sulfate, filtered and evaporated in vacuo to afford a residuethat was purified by flash chromatography (silica, 50 g column, Biotage,0-15% methanol in DCM) to afford the title compound as an off-whitesolid (137 mg, 30%). ¹H NMR (CDCl₃, 300 MHz): 12.41 (s, 1H), 9.04 (d,J=2.3 Hz, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.72 (d, J=1.0 Hz, 1H), 8.53 (s,1H), 7.76 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 3.65-3.56 (m, 4H),3.53 (s, 2H), 2.44-2.29 (m, 4H).

Step 2:6-(1-Methyl-1H-pyrazol-4-yl)-3-(4-morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-bromo-3-(4-morpholin-4-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(245 mg, 0.58 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(241 mg, 1.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (47 mg, 0.06 mmol) in 2N aqueous sodium carbonatesolution (7 mL) and acetonitrile (7 mL) was heated under microwaveirradiation at 130° C. for 20 minutes. The cooled reaction mixture wasdiluted with ethyl acetate (75 mL) and washed with water (50 mL). Theorganic phase was separated, dried over sodium sulfate, filtered andevaporated in vacuo to afford a residue that was purified by flashchromatography (silica, 10 g column, Biotage, 0-10% methanol in DCM) toafford the title compound as a white solid (61 mg, 25%). ¹H NMR (CDCl₃,300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.77 (d, J=2.2Hz, 1H), 8.31 (d, J=1.1 Hz, 1H), 8.07 (s, 1H), 8.05 (d, J=0.8 Hz, 1H),7.73-7.67 (m, 2H), 7.54-7.48 (m, 2H), 4.01 (s, 3H), 3.80-3.73 (m, 4H),3.63 (s, 2H), 2.60-2.52 (m, 4H).

Example 3756-(1-Methyl-1H-pyrazol-4-yl)-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:1-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-4-trifluoromethylpiperidine

A degassed mixture of 1-(4-bromobenzyl)-4-trifluoromethylpiperidine (1.0g, 3.1 mmol), bis(pinacolato)diborane (0.95 g, 3.7 mmol),1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.13 g,0.16 mmol) and potassium acetate (0.91 g, 9.3 mmol) in 1,4-dioxane (15mL) and DMSO (1 mL) was heated under microwave irradiation at 150° C.for 30 minutes. The cooled reaction mixture was partitioned betweenethyl acetate and water and the organic phase was separated, dried oversodium sulfate, filtered and evaporated to afford the title compound asa black oil (1.9 g) which was used without further purification. ¹H NMR(CDCl₃, 300 MHz): 7.79-7.74 (m, 2H), 7.32 (d, J=7.7 Hz, 2H), 3.71 (s,2H), 3.01-2.91 (m, 2H), 2.04-1.90 (m, 3H), 1.85-1.76 (m, 2H), 1.72-1.60(m, 2H), 1.34 (s, 12H). LCMS (Method B): R_(T)=2.53 min, M+H⁺=370.

Step 2:6-Bromo-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of 6-bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(0.64 g, 1.7 mmol),1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-4-trifluoromethylpiperidine (1.14 g, 3.1 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.21 g, 0.26 mmol) in2-methyl-THF (26 mL) and saturated aqueous sodium carbonate solution (12mL) was heated at 85° C. for 16 h. The cooled reaction mixture wasfiltered through celite and partitioned between DCM and water and thephases were separated. The organic phase was dried over sodium sulfate,filtered and evaporated then the residue was purified by flashchromatography (silica, 40 g column, ISCO, 0-15% methanol in DCM).Trituration of the resultant residue with acetonitrile afforded thetitle compound as a tan solid (57 mg, 7%). ¹H NMR (CD₃OD, 300 MHz): 8.84(d, J=2.2 Hz, 1H), 8.70-8.67 (m, 2H), 8.27 (d, J=1.0 Hz, 1H), 7.67 (d,J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.63 (s, 2H), 3.11-3.02 (m, 2H),2.14-2.02 (m, 3H), 1.94-1.84 (m, 2H), 1.76-1.59 (m, 2H. LCMS (Method B):R_(T)=2.55 min, M+H⁺=489.

Step 3:6-(1-Methyl-1H-pyrazol-4-yl)-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-bromo-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(0.15 g, 0.30 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(0.13 g, 0.60 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II)(25 mg, 0.03 mmol) inacetonitrile (3 mL) and saturated aqueous sodium carbonate solution (3mL) was heated under microwave irradiation at 130° C. for 30 minutes.The cooled reaction mixture was partitioned between DCM and water thenseparated on a hydrophobic frit. The organic phase was evaporated thenthe resultant residue was purified by flash chromatography (silica, 12 gcolumn, ISCO, 0-10% methanol in DCM) to afford a residue which waspurified by HPLC (C 18 column, 50-98% MeCN in water (plus 20 mMtriethylamine) to afford the title compound (46 mg, 31%). ¹H NMR(DMSO-D₆, 400 MHz): 12.15 (s, 1H), 8.94-8.88 (m, 2H), 8.86 (d, J=1.1 Hz,1H), 8.51 (d, J=1.1 Hz, 1H), 8.21 (s, 1H), 7.99 (d, J=0.8 Hz, 1H), 7.78(d, J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 3.92 (s, 3H), 3.56 (s, 2H),2.99-2.88 (m, 2H), 2.39-2.19 (m, 1H), 2.00 (t, J=1.5 Hz, 2H), 1.85-1.94(m, 2H), 1.57-1.38 (m, 2H). LCMS (Method A): R_(T)=5.22 min, M+H⁺=491.

Example 3763-[4-(4-Methoxypiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:4-Methoxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine

A degassed mixture of 1-(4-bromobenzyl)-4-methoxypiperidine (0.90 g,3.18 mmol), bis(pinacolato)diborane (0.89 g, 3.5 mmol),1,1′-[bis(diphenyl phosphino)ferrocene] dichloropalladium(II) (0.13 g,0.16 mmol) and potassium acetate (0.94 g, 9.5 mmol) in 1,4-dioxane (16mL) was heated under microwave irradiation at 150° C. for 30 minutes.The cooled reaction mixture was partitioned between ethyl acetate andwater, the organic phase was separated, dried over sodium sulfate,filtered through celite and evaporated to afford the title compound as abrown oil (1.07 g) which was used without further purification. ¹H NMR(CDCl₃, 300 MHz): 7.78 (d, J=7.5 Hz, 2H), 7.38 (d, J=7.5 Hz, 2H), 3.71(s, 2H), 3.64 (br s, 1H), 3.31 (s, 3H), 2.83-2.71 (m, 2H), 2.34 (br s,2H), 1.98 (br s, 2H), 1.69 (br s, 2H), 1.34 (s, 12H). LCMS (Method G):R_(T)=3.00 min, M+H⁺=332.

Step 2:6-Bromo-3-[4-(4-methoxypiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of 6-bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(0.50 g, 1.3 mmol),4-methoxy-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine(0.80 g, 2.4 mmol) and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.16 g, 0.2mmol) in 2-methyl THF (20 mL) and saturated aqueous sodium carbonate (10mL) was heated at 85° C. for 3 h. The material was partitioned betweenDCM, water and methanol and the phases were separated. The organic phasewas separated, dried over sodium sulfate, filtered and evaporated toafford a residue which was purified by flash chromatography (silica, 50g column, Biotage, 0-10% methanol in DCM). The resultant material wastriturated with methanol to afford the title compound as a tan solid(0.165 g, 28%). ¹H NMR (CDCl₃ plus CD₃OD, 300 MHz): 8.84 (d, J=2.2 Hz,1H), 8.73 (d, J=2.2 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.30 (d, J=1.0 Hz,1H), 7.68 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.63 (s, H),2.89-2.76 (m, 2H), 2.37-2.22 (m, 2H), 2.02-1.89 (m, 2H), 1.73-1.56 (m,2H). LCMS (Method G): R_(T)=3.30 min, M+H⁺=451.

Step 3:3-[4-(4-Methoxypiperidin-1-ylmethyl)-phenyl]-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-bromo-3-[4-(4-methoxypiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(0.16 g, 0.36 mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(0.15 g, 0.72 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.036 mmol) inacetonitrile (3.6 mL) and saturated aqueous sodium carbonate solution(3.6 mL). The reaction mixture was heated under microwave irradiation at130° C. for 20 minutes. The cooled reaction mixture was partitionedbetween DCM and water. The organic phase was dried over sodium sulfate,filtered and evaporated and the resultant residue was purified by flashchromatography (silica, 12 g column, ISCO, 0-15% methanol in DCM) toafford the title compound as a yellow solid (68 mg, 42%). ¹H NMR (CDCl₃plus CD₃OD, 300 MHz): 8.86 (d, J=1.1 Hz, 1H), 8.81 (d, J=2.2 Hz, 1H),8.77 (d, J=2.2 Hz, 1H), 8.30 (d, J=1.1 Hz, 1H), 8.06-8.04 (m, 2H), 7.71(d, J=7.9 Hz, 2H), 7.52 (d, J=2.0 Hz, 2H), 4.01 (s, 3H), 3.74-3.63 (m,2H), 2.94-2.79 (m, 2H), 2.47-2.25 (m, 2H), 2.04-1.90 (m, 2H), 1.78-1.58(m, 2H). LCMS (Method A): R_(T)=4.76 min, M+H⁺=453.

Example 3773-(3-Methoxy-4-piperidin-1-ylmethyl-phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6-Bromo-3-(3-methoxy-4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of1-[2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperidine(885 mg, 2.7 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(500 mg, 1.3 mmol),1,1′-[bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (163 mg,0.2 mmol) in 2N aqueous sodium carbonate solution (10 mL) and2-methyltetrahydrofuran (20 mL) was heated at 85° C. for 18 h. Thecooled reaction mixture was diluted with DCM (100 mL) and washed withwater (75 mL). The organic phase was separtated, dried over sodiumsulfate, filtered and evaporated in vacuo to afford a residue (357 mg,61%) that was used in the next step without purification. ¹H NMR (CDCl₃,300 MHz): 8.83 (d, J=2.0 Hz, 1H), 8.70 (s, 1H), 8.63 (d, J=2.0 Hz, 1H),8.24 (s, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.14 (s,1H), 3.96 (s, 3H), 3.65 (s, 2H), 2.56-2.48 (m, 4H), 1.67-1.59 (m, 4H),1.52-1.41 (m, 2H).

Step 2:3-(3-Methoxy-4-piperidin-1-ylmethylphenyl)-6-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-bromo-3-(3-methoxy-4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(350 mg, 0.78 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(242 mg, 1.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (64 mg, 0.08 mmol) in 2N aqueous sodium carbonatesolution (8 mL) and acetonitrile (8 mL) was heated under microwaveirradiation at 130° C. for 20 minutes. The cooled reaction mixture wasdiluted with ethyl acetate (75 mL) and washed with water (50 mL). Theorganic phase was separtated, dried over sodium sulfate, filtered andevaporated in vacuo to afford a residue that was purified by flashchromatography (silica, 50 g column, Biotage, 0-25% methanol in DCM) toafford the title compound as an off-white solid (61 mg, 17%). ¹H NMR(DMSO-D₆, 300 MHz): 8.95-8.92 (m, 2H), 8.85 (d, J=1.0 Hz, 1H), 8.49 (d,J=1.1 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.44 (d, J=7.7 Hz, 1H),7.38-7.33 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.48 (s, 2H), 2.44-2.34(m, 4H), 1.55-1.48 (m, 4H), 1.45-1.37 (m, 2H).

Example 3786-(Oxazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(150 mg, 0.36 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (140 mg, 0.71mmol), 1,1′-[bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (29mg, 0.004 mmol) in saturated aqueous sodium carbonate solution (0.5 mL)and acetonitrile (5 mL) was heated under microwave irradiation at 130°C. for 30 minutes. The cooled reaction mixture was diluted with DCM (20mL) and methanol (2 mL) and washed with water (15 mL). The organic phasewas separated, dried over sodium sulfate, filtered and evaporated invacuo to afford a residue that was purified by preparative HPLC [20-60%MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] toafford the title compound as an off-white solid (42 mg, 29%). ¹H NMR(DMSO-D₆, 400 MHz): 12.42 (s, 1H), 9.12 (d, J=2.2 Hz, 1H), 8.96 (s, 1H),8.94 (d, J=2.2 Hz, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 7.78 (d, J=8.1 Hz,2H), 7.66 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H),1.51 (m, 4H), 1.40 (m, 2H). LCMS (Method D): R_(T)=7.76 min, M+H⁺=410.

Example 3796-(1-Methyl-1H-pyrazol-5-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole toyield a yellow/orange solid (20%). ¹H NMR (DMSO-D₆, 400 MHz): 12.34 (s,1H), 9.05 (d, J=2.2 Hz, 1H), 9.00 (s, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.65(s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.50 (d, J=1.9 Hz, 1H), 7.45 (d, J=8.2Hz, 2H), 6.72 (d, J=1.9 Hz, 1H), 4.17 (s, 3H), 3.49 (s, 2H), 2.35 (s,4H), 1.51 (m, 4H), 1.42 (m, 2H). LCMS (Method D): R_(T)=6.48 min,M+H⁺=423.

Example 3806-(1-Methyl-1H-imidazol-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(100 mg, 0.16 mmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (120 mg,0.32 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol)and lithium chloride (68 mg, 1.6 mmol) in 1,4-dioxane (3 mL) wasdegassed and flushed with nitrogen and the reaction heated at 100° C.for 16 h. The cooled reaction mixture was diluted with DCM (20 mL) andmethanol (2 mL) and washed with water (15 mL). The organic phase wasseparated, dried over sodium sulfate, filtered and evaporated in vacuoto afford a residue that was purified by flash chromotagraphy (silica,10 g column, Biotage, 0-10% methanol in (DCM containing 1% 7M ammonia inmethanol)) to afford a residue that was purified by preparative HPLC[20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min]to afford the title compound as a pale orange solid (13 mg, 20%). ¹H NMR(DMSO-D₆, 400 MHz): 12.26 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.95 (d,J=0.9 Hz, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.58 (d, J=0.9 Hz, 1H), 7.77 (d,J=8.2 Hz, 2H), 7.72 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.39 (d, J=1.0 Hz,1H), 3.96 (s, 3H), 3.49 (s, 2H), 2.36 (s, 4H), 1.57-1.47 (m, 4H), 1.40(m, 2H). LCMS (Method D): R_(T)=6.54 min, M+H⁺=423.

Example 3816-(Thiazol-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure as to theprevious example using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole to yield a beigesolid (21%). ¹H NMR (DMSO-D₆, 400 MHz): 12.32 (s, 1H), 9.08 (s, 1H),9.00 (d, J=2.4 Hz, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.92 (s, 1H), 8.89 (s,1H), 8.49 (s, 1H), 8.25 (s, 2H), 7.78 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.1Hz, 3H), 3.50 (s, 2H), 2.37 (s, 4H), 1.53 (m, 4H), 1.40 (m, 2H). LCMS(Method D): R_(T)=8.36 min, M+H⁺=426.

Example 3826-(Isoxazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-bromo-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(130 mg, 0.18 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (140 mg, 0.74mmol), 1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (18mg, 0.002 mmol) in 1N aqueous potassium acetate solution (0.62 mL) andacetonitrile (3 mL) was heated under microwave irradiation at 85° C. for18 minutes. The cooled reaction mixture was diluted with DCM (20 mL) andmethanol (2 mL) and washed with water (15 mL). The organic phase wasseparated, dried over sodium sulfate, filtered and evaporated in vacuoto afford a residue that was purified by preparative HPLC [0-30% MeCN inwater (0.1% formic acid) over 30 min, 35 mL/min] to afford the titlecompound as a beige solid (10 mg, 10%). ¹H NMR (DMSO-D₆, 400 MHz): 12.32(s, 1H), 9.47 (s, 1H), 9.18 (s, 1H), 8.95 (s, 1H), 8.94 (d, J=2.3 Hz,1H), 8.89 (d, J=2.2 Hz, 1H), 8.68 (s, 1H), 7.76 (d, J=8.1 Hz, 2H), 7.45(d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.52 (m, 4H), 1.41 (m,2H). LCMS (Method D): R_(T)=6.55 min, M+H⁺=410.

Example 3836-(3,5-Dimethylisoxazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b:4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole toyield an off-white solid (20%). ¹H NMR (DMSO-D₆, 500 MHz): 12.32 (s,1H), 9.09 (d, J=2.3 Hz, 1H), 9.00 (d, J=1.0 Hz, 1H), 8.93 (d, J=2.3 Hz,1H), 8.41 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.45 (d, J =8.2 Hz, 2H), 3.49(s, 2H), 2.63 (s, 3H), 2.45 (s, 3H), 2.36 (s, 4H), 1.51 (m, 4H), 1.40(m, 2H). LCMS (Method D): R_(T)=6.44 min, M+H⁺=438.

Example 3846-(2-Methylthiazol-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using 2-methyl-5-(trimethylstannyl)thiazole to yield apale yellow solid (20%). ¹H NMR (DMSO-D₆, 400 MHz): 12.35 (s, 1H), 8.99(d, J=2.2 Hz, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.89 (s, 1H), 8.82 (s, 1H),8.21 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.49 (s,2H), 2.69 (s, 3H), 2.36 (s, 4H), 1.57-1.47 (m, 4H), 1.41 (m, 2H). LCMS(Method D): R_(T)=7.42 min, M+H⁺=440.

Example 3856-(1,2-Dimethyl-1H-imidazol-5-yl-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using 1,2-dimethyl-5-(tributylstannyl)-1H-imidazole toyield a pale yellow solid (20%). ¹H NMR (DMSO-D₆, 500 MHz): 12.25 (s,1H), 9.04 (d, J=2.1 Hz, 1H), 8.95 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.51(s, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H), 7.21 (s, 1H),3.86 (s, 3H), 3.49 (s, 2H), 2.38 (s, 3H), 2.36 (s, 4H), 1.51 (m, 4H),1.40 (m, 2H). LCMS (Method D): R_(T)=6.72 min, M+H⁺=437.

Example 3866-(1,3,4-Thiadiazol-2-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:3-(4-Piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbhydrazide

A solution of3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylicacid methyl ester (425 mg, 1.06 mmol) and hydrazine hydrate (1.29 mL,26.5 mmol) in ethanol (4.6 mL) was heated under reflux for 1 h under anitrogen atmosphere. The solution was allowed to cool to ambienttemperature and the resulting precipitate was collected by filtration,washed with ethanol, and dried under vacuum to afford a yellow solid(337 mg, 79%). The solid was used without purification.

Step 2:6-(1,3,4-Thiadiazol-2-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbhydrazide(87.3 mg, 0.218 mmol) in formic acid (1.0 mL) was heated under refluxfor 30 minutes then allowed to cool to room temperature, diluted withxylenes (4.4 mL) and treated with phosphorus pentasulfide (174 mg, 0.392mmol). The mixture was heated under reflux under a nitrogen atmospherefor 24 h, then allowed to cool to ambient temperature and treated withadditional phosphorus pentasulfide (116 mg, 0.263 mmol) and formic acid(1.0 mL). The mixture was heated under reflux for an additional 24 h,allowed to cool, and concentrated in vacuo. The resulting residue waspurified by preparative HPLC (2-60% MeCN/water modified with 0.1%ammonium hydroxide) to afford the title compound as an orange fluffysolid (9.5 mg, 10%). ¹H NMR (DMSO-D₆, 400 MHz): 12.63-12.59 (s, 1H),9.62 (s, 1H), 9.26 (s, 1H), 9.24 (d, J=2.2 Hz, 1H), 9.02 (s, 1H), 8.98(d, J=2.2 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.50(s, 2H), 2.38 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D):R_(T)=8.71 min, M+H⁺=427.

Example 3876-(1,3,4-Oxadiazol-2-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A solution of3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbhydrazide(53.8 mg, 0.134 mmol) and trimethoxymethane (1.21 mL, 11.0 mmol) in DMF(0.81 mL) was heated at 120° C. for 24 h. The mixture was cooled,treated with trimethoxymethane (1.0 mL) and a few drops of acetic acidand heated under reflux for 48 h. The mixture was allowed to cool,treated with saturated aqueous sodium bicarbonate solution, and theresultant white precipitate collected by filtration and washed withwater. The filtrate was extracted with DCM, 20% methanol in DCM, and thecombined organic phases dried over sodium sulfate, combined with theisolated solid and concentrated in vacuo. The resultant residue waspurified by preprative HPLC [2-60% MeCN/water modified with 0.1%ammonium hydroxide] to afford a light-yellow flaky solid (6.0 mg, 27%).¹H NMR (DMSO-D₆, 400 MHz): 12.77-12.69 (s, 1H), 9.41 (s, 1H), 9.26 (d,J=2.2 Hz, 1H), 9.18 (s, 1H), 9.08 (s, 1H), 9.00 (d, J=2.2 Hz, 1H), 8.31(s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H),2.37 (m, 414), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): R_(T)=7.69min, M+H⁺=411.

Example 3886-(1-Benzyl-1H-1,2,3-triazol-4-yl)₃-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:64(Trimethylsilyl)ethynyl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-bromo-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(170 mg, 0.40 mmol), copper(I) iodide (7.7 mg, 0.04 mmol), and AN,N-diisopropylethylamine (0.21 mL, 1.2 mmol) in anhydrous 1,4-dioxane(3 mL) was degassed and flushed with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.04 mmol) and(trimethylsilyl)acetylene (0.34 mL, 2.4 mmol) were added and thereaction mixture heated at 110° C. for 1 h. The cooled reaction mixturewas diluted with DCM (20 mL) and methanol (2 mL) and washed with water(15 mL). The organic phase was separated, dried over sodium sulfate,filtered and evaporated in vacuo to afford a residue that was purifiedby flash chromotagraphy (silica, 10 g column, Biotage, 0-10% methanol in(DCM containing 1% 7M ammomia in methanol) to afford a brown residuethat was taken to the next step without further purification.

Step 2:6-Ethynyl-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-((trimethylsilyl)ethynyl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(120 mg, 0.3 mmol) and potassium carbonate (170 mg, 1.2 mmol) inmethanol (2 mL) was stirred at ambient temperature for 1 h. The reactionmixture was diluted with DCM (20 mL) and methanol (2 mL) and washed withwater (15 mL). The organic phase was separated, dried over sodiumsulfate, filtered and evaporated in vacuo to afford a brown residue thatwas taken to the next step without purification.

Step 3:6-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-ethynyl-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(90 mg, 0.2 mmol), copper (I) iodide (4.7 mg, 0.02 mmol), andazidomethyl-benzene (36 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL)was heated at 60° C. for 2 h. The cooled reaction mixture was dilutedwith DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). Theorganic phase was separated, dried over sodium sulfate, filtered andevaporated in vacuo to afford a residue that was purified by preparativeHPLC [20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35mL/min] to afford the title compound as an off-white solid (20 mg, 20%).¹H NMR (DMSO-D₆, 400 MHz): 12.30 (s, 1H), 9.16 (d, J=2.2 Hz, 1H), 8.93(s, 2H), 8.91 (s, 1H), 8.61 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.40 (m,7H), 5.69 (s, 2H), 3.49 (s, 2H), 2.36 (s, 4H), 1.57-1.46 (m, 4H), 1.40(m, 2H). LCMS (Method D): R_(T)=9.35 min, M+H⁺=500.

Example 3896-(1H-1,2,3-Triazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6′-((Trimethylsilyl)ethynyl)-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4′]bipyridinyl-3′-ylamine

A mixture of6′-bromo-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4′b]ipyridinyl-3′-ylamine(100 mg, 0.23 mmol), copper (I) iodide (4.3 mg, 0.02 mmol), andN,N-diisopropylethylamine (0.08 mL, 0.45 mmol) in anhydrous 1,4-dioxane(2.5 mL) was degassed and flushed with nitrogen.Tetrakis(triphenylphosphine)palladium(0) (26 mg, 0.02 mmol) and(trimethylsilyl)acetylene (0.16 mL, 1:1 mmol) were added and thereaction was heated at 100° C. for 5 h. The cooled reaction mixture wasdiluted with DCM (20 mL) and methanol (2 mL) and washed with water (15mL). The organic phase was separated, dried over sodium sulfate,filtered and evaporated in vacuo to afford a residue that was purifiedby flash chromotagraphy (silica, 10 g column, Biotage, 0-10% methanol in(DCM containing 1% 7M ammonia in ammonia)) to afford a brown residuethat was taken to the next step without further purification.

Step 2:6′-Ethynyl-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4′]bipyridinyl-3′-ylamine

A mixture of6′-((trimethylsilyl)ethynyl)-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine(90 mg, 0.2 mmol) and potassium carbonate (150 mg, 1.1 mmol) in methanol(2 mL) was stirred at ambient temperature for 1 h. The cooled reactionmixture was diluted with DCM (20 mL) and methanol (2 mL) and washed withwater (15 mL). The organic phase was separated, dried over sodiumsulfate, filtered and evaporated in vacuo to afford a brown residue thatwas taken to the next step without purification.

Step 3:6-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6′-ethynyl-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4]bipyridinyl-3′-ylamine(60 mg, 0.16 mmol), copper (I) iodide (3.0 mg, 0.016 mmol), andazidomethylbenzene (29 mg, 0.22 mmol) in N,N-dimethylformamide (2 mL)was heated at 60° C. for 2 h. The cooled reaction mixture was dilutedwith DCM (20 mL) and methanol (2 mL) and washed with water (15 mL). Theorganic phase was separated, dried over sodium sulfate, filtered andevaporated in vacuo to afford a brown residue that was taken to the nextstep without purification.

Step 4:6-(1H-1,2,3-Triazol-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

To a solution of6′-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4′]bipyridinyl-3′-ylamine(80 mg, 0.16 mmol) in anhydrous tetrahydrofuran (2 mL) was added sodiumbis(trimethylsilyl)amide (1N solution in THF, 0.46 mL, 0.46 mmol) undera flow of nitrogen and the reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was then evaporated in vacuoto afford a residue that was purified by preparative HPLC (20-60% MeCNin water (0.1% ammonium hydroxide) over 30 min, 35 mL/min) to afford thetitle compound as an orange solid (10 mg, 10%). ¹H NMR (DMSO-D₆, 500MHz):12.33 (s, 1H), 9.12 (s, 1H), 8.95 (s, 1H), 8.94 (d, J=2.2 Hz, 1H),8.88 (s, 1H), 8.31 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.0 Hz,2H), 3.49 (s, 2H), 2.36 (s, 4H), 1.52 (m, 4H), 1.41 (m, 2H), triazole NHnot observed. LCMS (Method D): R_(T)=6.68 min, M+H⁺=410.

Example 3906-(Tetrazol-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-carbonitrile-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(269 mg, 0.732 mmol) and azidotrimethyltin(IV) (1.51 g, 7.32 mmol) in amixture of N,N-dimethylacetamide (5 mL) and toluene (24 mL) was heated110° C. for 24 hours. The reaction mixture was allowed to cool andconcentrated in vacuo. The resultant residue was dissolved in 20%methanol in DCM, absorbed onto celite in vacuo, and purified by flashchromatography (Amino Silica, Snap KP-NH, Biotage, 1-20% methanol in(DCM containing 0 1% 7M ammonia in methanol) to yield a dark yellowsolid (80.5 mg). The solid was further purified by preparative HPLC(2-60% MeCN/water containing 0.1% ammonium hydroxide) to afford thetitle compound as a pale yellow solid (36.9 mg, 12%). ¹H NMR (DMSO-D₆,400 MHz): 12.52 (s, 1H), 9.22 (d, J=2.2 Hz, 1H), 9.10 (s, 1H), 9.02 (s,1H), 8.98 (d, J=2.2 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.1 Hz,2H), 3.69 (s, 2H), 2.55 (m, 4H), 1.58 (m, 4H), 1.44 (m, 2H). LCMS(Method E): R₁=3.04 min, M+H⁺=411.

Example 3916-Pyridin-3-yl-3-[4-(4-trifluoromethylpiperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

To a mixture of pyridine-2-boronic acid (27 mg, 0.22 mmol),6-bromo-3-[4-(4-trifluoromethyl-piperidin-1-ylmethyl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(55 mg, 0.11 mmol) and1,1′-[bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (9 mg,0.011 mmol) in acetonitrile (1 mL) and saturated aqueous sodiumcarbonate solution (1 mL) was heated under microwave irradiation at 140°C. for 30 minutes. The cooled reaction mixture was partitioned betweenDCM and water and the phases were separated using a hydrophobic fit andthe organic phase evaporated. The residue was purified HPLC (C18 column,50-98% MeCN in water (containing 20 mM triethylamine) over 30 minutesand the fractions containing pure product combined and concentrated thenfreeze-dried to afford the title compound (6 mg, 11%). ¹H NMR (CDCl₃plus CD₃OD, 400 MHz): 9.22 (dd, J=2.3, 0.8 Hz, 1H), 9.05 (d, J=1.1 Hz,1H), 8.86-8.83 (m, 2H), 8.59-8.56 (m, 2H), 8.48-8.44 (m, 1H), 7.73-7.69(m, 2H), 7.58-7.54 (m, 1H), 7.50 (d, J=8.0 Hz, 2H), 3.64 (s, 2H),3.11-3.03 (m, 2H), 2.17-2.04 (m, 3H), 1.93-1.85 (m, 2H), 1.74-1.61 (m,2H). LCMS (Method A): R_(T)=5.43 min, M+H⁺=488.

Example 3926-(Pyridin-3-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using 3-(1,3,2-dioxaborinan-2-yl)pyridine to yield abeige solid (40%). NMR (DMSO-D₆, 400 MHz): 12.30 (s, 1H), 9.36 (d, J=2.0Hz, 1H), 9.05 (d, J=2.3 Hz, 1H), 9.04 (s, 1H), 8.99 (s, 1H), 8.94 (d,J=2.2 Hz, 1H), 8.60 (dd, J=1.6 Hz, 3.2, 1H), 8.50 (dt, J=8.0, 2.0 Hz,1H), 7.78 (d, J=8.2 Hz, 2H), 7.55 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 3.51(s, 2H), 2.38 (s, 4H), 1.53 (m, 4H), 1.41 (m, 2H). LCMS (Method D):R_(T)=6.92 min, M+H⁺=420.

Example 3936-(Pyridin-3-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using pyridin-4-ylboronic acid to yield a beige solid(40%). ¹H NMR (DMSO-D₆, 400 MHz): 12.48 (s, 1H), 9.10 (s, 1H), 9.07 (d,J=2.2 Hz, 1H), 9.06 (s, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.70 (d, J=6.1 Hz,2H), 8.15 (d, J=6.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz,2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.58-1.47 (m, 4H), 1.41 (m, 2H). LCMS(Method D): R_(T)=7.01 min, M+H⁺=420.

Example 3946-(4-Methoxypyridin-3-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using 5-4-methoxypyridin-3-ylboronic acid to yield abeige solid (20%). ¹H NMR (DMSO-D₆, 500 MHz): 12.36 (s, 1H), 9.05 (d,J=2.2 Hz, 1H), 9.03 (s, 1H), 8.93 (d, J=2.1 Hz, 1H), 8.87 (s, 1H), 8.71(s, 1H), 8.48 (d, J=5.7 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1Hz, 2H), 7.24 (d, J=5.8 Hz, 1H), 3.99 (s, 3H), 3.49 (s, 2H), 2.36 (s,4H), 1.57-1.47 (m, 4H), 1.40 (m, 2H). LCMS (Method D): R_(T)=6.56 min,M+H⁺=450.

Example 3956-(5-Methoxypyridin-3-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-bl4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using3-methoxy-5-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)pyridine toafford a beige solid (20%). ¹H NMR (DMSO-D₆, 500 MHz): 12.39 (s, 1H),9.05 (d, J=2.5 Hz, 1H), 9.04 (s, 1H), 9.03 (s, 1H), 8.99 (s, 1H), 8.95(d, J=2.5 Hz, 1H), 8.32 (d, J=2.8 Hz, 1H), 8.08 (s, 1H), 7.78 (d, J=8.1Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 3.96 (s, 3H), 3.50 (s, 2H), 2.36 (s,4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): R_(T)=7.68 min,M+H⁺=450.

Example 3963-(1-Methyl-1H-pyrazol-4-yl)-6-[4-(piperidin-4-yloxy)-pyridin-3-yl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6-Iodo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-bromo-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.20 g, 0.44 mmol),copper (I) iodide (8.9 mg, 0.044 mmol), N,N′-dimethylethylenediamine(9.4 μL, 0.088 mmol) and sodium iodide (0.264 mg, 1.76 mmol) in1,4-dioxane (2 mL) was heated at 110° C. for 3 days. The cooled reactionmixture was partitioned between water and ethyl acetate, the organiclayer was separated, dried over sodium sulfate, filtered and evaporatedto afford the title compound as a yellow solid (0.205 g, 92%). 1H NMR(CDCl₃, 300 MHz): 8.88 (d, J=0.9 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H),8.41-8.36 (m, 2H), 7.84 (s, 1H), 7.71 (s, 1H), 5.92 (s, 2H), 4.02 (s,3H), 3.58 (t, J=8.2 Hz, 2H), 0.92 (t, J=8.2 Hz, 2H), −0.09 (s, 9H).

Step 2:6-(4-Chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

6-Iodo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(0.21 g, 0.41 mmol), 4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.15 g, 0.615 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloro palladium(II) (17 mg,0.021 mmol) in saturated aqueous sodium carbonate solution (1 mL) andacetonitrile (4 mL) were placed under an atmosphere of argon and heatedwith microwave irradiation at 100° C. for 45 minutes. The cooledreaction mixture was diluted with water and extracted with ethylacetate. The organic layer was separated, dried over sodium sulfate,filtered and evaporated to afford a residue which was purified by flashchromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) toafford the title compound as a yellow oil (0.13 g, 66%). ¹H NMR (CDCl₃,400 MHz): 9.22 (d, J=1.1 Hz, 1H), 8.91 (d, J=0.5 Hz, 1H), 8.79 (d, J=2.1Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.32 (d, J=1.1Hz, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.73 (s, 1H), 7.48 (dd, J=5.4, 0.5 Hz,1H), 6.01 (s, 2H), 4.01 (s, 3H), 3.70-3.63 (m, 2H), 1.02-0.94 (m, 2H),−0.06 (s, 9H). LCMS (Method G): R_(T)=4.8 min, M+H⁺=491.

Step 3:4-{3-[3-(1-Methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl]-pyridin-4-yloxy}-piperidine-1-carboxylicacid tert-butyl ester

Sodium hydride (60% dispersion in mineral oil, 42 mg, 1.06 mmol) wasadded to a solution of tert-butyl-4-hydroxy-1-piperidinecarboxaldehyde(0.16 g, 0.795 mmol) in DMF (2.5 mL) and the reaction mixture wasstirred at ambient temperature for 30 minutes.6-(4-Chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(0.13 g, 0.265 mmol) was added as a solution in DMF (2.5 mL) and thereaction mixture was heated at 80° C. for 1.5 h. The material waspartitioned between water and ethyl acetate. The organic layer wasseparated, dried over sodium sulfate, filtered and evaporated in vacuo.The resultant residue was purified by flash chromatography (silica, 12 gcolumn, ISCO, 0-10% methanol in DCM) to afford the title compound as ayellow oil which crystallised on standing (0.1 g, 58%). ¹H NMR (CDCl₃,400 MHz): 9.19 (d, J=1.1 Hz, 1H), 9.01 (s, 1H), 8.79 (d, J=2.1 Hz, 1H),8.51 (d, J=5.7 Hz, 1H), 8.45 (d, J=1.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H),7.85 (s, 1H), 7.76 (s, 1H), 6.97 (d, J=5.8 Hz, 1H), 6.01 (s, 2H),4.84-4.73 (br s, 1H), 4.02 (s, 3H), 3.71-3.62 (m, 2H), 3.60-3.39 (m,4H), 1.97 (br s, 2H), 1.88 (br s, 2H), 1.41 (s, 9H), 1.01-0.93 (m, 2H),−0.07 (s, 9H).

Step 4:3-(1-Methyl-1H-pyrazol-4-yl)-6-[4piperidin-4-yloxy)-pyridin-3-yl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of4-{3-[3(1-methyl-1H-pyrazol-4-yl)-942-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl]-pyridin-4-yloxy}-piperidine-1-carboxylicacid tert-butyl ester (0.1 g, 0.15 mmol) in TBAF (1N in THF, 10 mL) washeated at 50° C. for 19 h. The cooled reaction mixture was partitionedbetween water and ethyl acetate. The organic layer was separated, driedover sodium sulfate, filtered and concentrated in vacuo, to afford aresidue which was purified by flash chromatography (silica, 12 g column,ISCO, 0-10% methanol in DCM). This resultant residue was dissolved inDCM (5 mL) and TFA (1 mL) and left to stir for 30 minutes. The mixturewas diluted with DCM and water. The aqueous layer was separated,evaporated and the resultant residue was loaded onto an SCX-2 cartridgeand washed with methanol and 2M ammonia in methanol. The combined basicfraction was purified by HPLC (C18 column, eluting with 5-60% MeCN inwater (with 20 mM triethylamine) over 20 minutes) to afford the titlecompound as a white solid (25 mg, 39%). ¹H NMR (MeOD, 400 MHz): 8.97 (s,1H), 8.83-8.78 (m, 2H), 8.72 (s, 1H), 8.58 (s, 1H), 8.43 (d, J=5.9 Hz,1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.28 (d, J=6.0 Hz, 1H), 4.91-4.80 (m,1H), 3.98 (s, 3H), 3.01-2.91 (m, 2H), 2.80-2.70 (m, 2H), 2.11-2.00 (m,2H), 1.83-1.73 (m, 2H) plus 2 exchangeables not observed. LCMS (MethodA): R_(T)=4.0 min, M+H⁺=426.

Example 3976-[4-(1-Ethyl-piperidin-4-yloxy)-pyridin-3-yl]-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Sodium hydride (60% dispersion in mineral oil, 0.133 g, 3.32 mmol) wasadded to a solution of 1-ethyl-piperidin-4-ol (0.306 g, 2.37 mmol) inDMF (5 mL) and the reaction mixture was stirred at ambient temperaturefor 45 minutes.6-(4-Chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(0.121 g, 0.474 mmol) was added and the reaction mixture was heated at80° C. for 5 h. The material was partitioned between water and ethylacetate. The solid suspended in the aqueous layer was removed byfiltration then the aqueous layer was separated, adsorbed onto HM-N andpurified by flash chromatography (silica, 12 g column, ISCO, 0-10% (2Nammonia in methanol) in DCM). The resultant residue was triturated withethyl acetate and cyclohexane to afford the title compound as a yellowsolid (28 mg, 13%). ¹H NMR (MeOD, 400 MHz): 8.97 (d, J=1.1 Hz, 1H),8.83-8.80 (m, 2H), 8.73 (s, 1H), 8.60 (d, J=1.1 Hz, 1H); 8.43 (d, J=5.9Hz, 1H), 8.11 (s, 1H), 7.97 (d, J=0.8 Hz, 1H), 7.28 (d, J =6.0 Hz, 1H),3.98 (s, 3H), 2.65-2.54 (m, 2H), 2.53-2.43 (m, 2H), 2.39 (q, J=7.3 Hz,2H), 2.13-2.03 (m, 2H), 1.97-1.86 (m, 2H), 1.02 (t, J=7.2 Hz, 3H). LCMS(Method A): R_(T)=4.0 min, M+H⁺=454.

Example 398Dimethyl-(2-{3-[3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-yl]-pyridin-4-yloxy}-ethyl)-amine

Sodium hydride (60% dispersion in mineral oil, 38 mg, 0.96 mmol) wasadded to a solution of N,N-dimethylethanolamine (63 mg, 0.71 mmol) inDMF (5 mL) and the mixture stirred at ambient temperature for 75minutes.6-(4-chloro-pyridin-3-yl)-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(85 mg, 0.24 mmol) was added and the reaction mixture was stirred atambient temperature for 26 h then at 80° C. for 2 h. After this time,the reaction mixture was added to a solution of N,N-dimethylethanolamine(0.48 mL) and sodium hydride (60% dispersion in mineral oil, 288 mg) inDMF (2 mL), which had been pre-stirred for 15 minutes. The reactionmixture was stirred at 80° C. overnight before being poured onto waterand the resultant solid collected by filtration. The material waspurified by flash chromatography (silica, 12 g column, ISCO, 0-20%methanol in DCM then 20% (2N ammonia in methanol) in DCM) to afford thetitle compound as a yellow oil which crystallised on standing (0.1 g,58%). ¹H NMR (CD₃OD, 400 MHz): 8.94 (d, J=1.1 Hz, 1H), 8.81-8.77 (m,2H), 8.71 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.48 (d, J=5.9 Hz, 1H), 8.09(s, 1H), 7.94 (s, 1H), 7.28 (d, J=5.9 Hz, 1H), 4.42 (t, J=5.2 Hz, 2H),3.98 (s, 3H), 3.03 (t, J=5.1 Hz, 2H), 2.42 (s, 6H). LCMS (Method A):R_(T)=3.93 min, M+H⁺=414.

Example 3996-(Pyrazin-2-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using 2-(tributylstannyl)pyrazine to yield a paleorange solid (20%). ¹H NMR (DMSO-D₆, 500 MHz): 12.43 (s, 1H), 9.62 (d,J=1.4 Hz, 1H), 9.28 (s, 1H), 9.19 (d, J=2.3 Hz, 1H), 9.06 (s, 1H), 8.95(d, J=2.2 Hz, 1H), 8.78-8.72 (m, 1H), 8.66 (d, J=2.5 Hz, 1H), 7.81 (d,J=8.2 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H),1.58-1.48 (m, 4H), 1.41 (m, 2H). LCMS (Method E): R_(T)=2.93 min,M+H⁺=421.

Example 4006-(Pyridazin-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

Step 1:6′-(Pyridazin-4-yl)-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4′]bipyridinyl-3′-ylamine

A mixture of6′-bromo-2-fluoro-5-(4-piperidin-1-ylmethylphenyl)-[3,4]bipyridinyl-3′-ylamine(200 mg, 0.45 mmol), 4-(tributylstannyl)pyridazine (334 mg, 0.91 mmol)and lithium chloride (192 mg, 4.5 mmol) in 1,4-dioxane (5 mL) wasdegassed and flushed with nitrogen.Tetrakis(triphenylphosphine)-palladium(0) (39 mg, 0.034 mmol) was addedand the reaction was heated at 110° C. for 24 h. The cooled reactionmixture was diluted with DCM (20 mL) and methanol (2 mL) and washed withwater (15 mL). The organic phase was separated, dried over sodiumsulfate, filtered and evaporated in vacuo to afford a residue that waspurified by flash chromotagraphy (silica, 10 g column, Biotage, 0-10%methanol in DCM containing 0 1% ammonia) to afford a brown residue thatwas taken to the next step without further purification.

Step 2:6-(Pyridazin-4-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

To a solution of6′-(pyridazin-4-yl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (120 mg, 0.27mmol) in anhydrous tetrahydrofuran (5 mL) was added sodiumbis-(trimethylsilyl)amide (1N solution in THF, 1.4 mL, 1.4 mmol) under aflow of nitrogen. The reaction was left to stir at room temperature for5 h then quenched with acetic acid (1 mL). The reaction mixture was thenevaporated in vacuo to afford a residue that was purified by preparativeHPLC [20-60% MeCN in water (0.1% ammonium hydroxide) over 30 min, 35mL/min] to afford the title compound as a pale orange solid (37 mg,20%). ¹H NMR (DMSO-D₆, 400 MHz): 12.58 (s, 1H), 10.01 (s, 1H), 9.35 (d,J=5.4 Hz, 1H), 9.25 (s, 1H), 9.12 (s, 1H), 9.05 (d, J=2.1 Hz, 1H), 8.98(d, J=2.1 Hz, 1H), 8.34 (m, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1Hz, 2H), 3.52 (s, 2H), 2.38 (s, 4H), 1.53 (m, 4H), 1.41 (m, 2H). LCMS(Method D): R_(T)=7.78 min, M+H⁺=421.

Example 4016-(pyrimidin-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A mixture of6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(40 mg, 0.08 mmol), pyrimidin-5-yl boronic acid (20 mg, 0.16 mmol),1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.2 mg,0.004 mmol) in saturated aqueous sodium carbonate solution (0.15 mL) andacetonitrile (1.50 mL) was heated under microwave irradiation at 130° C.for 30 minutes. The cooled reaction mixture was diluted with DCM (20 mL)and methanol (2 mL) and washed with water (15 mL). The organic phase wasseparated, dried over sodium sulfate, filtered and evaporated in vacuoto afford a residue that was purified by preparative HPLC [0-30% MeCN inwater (0.1% formic acid) over 30 min, 35 mL/min] to afford the titlecompound as a yellow/orange solid (10 mg, 23%). ¹H NMR (DMSO-D₆, 400MHz): 12.44 (s, 1H), 9.52 (s, 2H), 9.21 (s, 1H), 9.08 (d, J=1.7 Hz, 2H),9.02 (d, J=2.2 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 2H),7.46 (d, J=8.1 Hz, 2H), 3.50 (s, 2H), 2.37 (s, 4H), 1.53 (m, 4H), 1.41(m, 2H). LCMS (Method D): R_(T)=6.84 min, M+H⁺=421.

Example 4026-(2-Aminopyrimidin-5-yl)-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

A degassed mixture of6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole(74.4 mg, 0.197 mmol), 2-aminopyrimidine-5-boronic acid, pinacol ester(45.8 mg, 0.207 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (8.1 mg, 9.87umol, 5.0 mol %) in acetonitrile (0.74 mL) and 1M aqueous potassiumcarbonate solution (0.74 mL) was heated under microwave irradiation(140° C.) for 30 minutes. Further portions of the boronate ester (1.0eq) and catalyst (5 mol %), acetonitrile (0.74 mL), and 1M aqueouspotassium carbonate solution (0.74 mL) were added and the mixture heatedunder microwave irradiation (140° C.) for an additional 30 minutes. Themixture was concentrated in vacuo and the residue dissolved in water andDMF, and acidified with 10% (v/v) sulfuric acid. The resultant solid wasremoved by filtration and the filtrate concentrated in vacuo. Theresultant residue was dissolved in DMSO and purified by preparative HPLC[0-30% MeCN/water modified with 0.1% formic acid] to afford an orangefluffy solid (5.1 mg, 14%). LCMS (Method E): R_(T)=5.45 min, M+H⁺=436.

Example 4036-(Imidazo[1,2-a]pyrimidin-3-yl)-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole

The title compound was prepared following a similar procedure to theprevious example using 3-(trimethylstannyl)imidazo[1,2-a]pyrimidine toyield a pale yellow solid (20%). ¹H NMR (DMSO-D₆, 400 MHz): 12.34 (s,1H), 10.23 (dd, J=6.8, 2.0 Hz, 1H), 9.05 (s, 1H), 9.04 (d, J=2.4 Hz,1H), 8.97 (d, J=2.4 Hz, 1H), 8.95 (s, 1H), 8.64 (s, 1H), 8.46 (s, 1H),7.79 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.25 (s, 1H), 3.52 (s,2H), 2.39 (s, 4H), 1.54 (m, 4H), 1.42 (m, 2H). LCMS (Method D):R_(T)=7.32 min, M+H⁺=460.

Example i Chk1 and Chk2 Assays (Chk Primary Assays)

Full length human mutant recombinant protein, histidine tagged andexpressed in insect cells is used as source of enzymatic activity(Invitrogen, chk1 from product PV3982 and chk2 from product PV3983).

The chk1 AlphaScreen assay is carried out for 30 minutes in the presenceof 10 μM ATP using biotinylated Akt substrate-1 peptide (Cell SignallingTechnology, product #1065) as a substrate. Phosphorylation of thesubstrate is detected and quantified using AlphaScreen technology. Thisconsists of an anti-phospho-Akt substrate-1 antibody (Cell Signallingtechnology Product #9611) and two AlphaScreen beads (Perkin Elmer), oneproduct coated with Protein A which binds the antibody Ig chain (Product6760137), and one coated with Streptavidin which binds the biotin on thebiotinylated Akt substrate peptide-1 (Product 6760002). Chk1 activityresults in the production of phosphorylated Akt substrate peptide-1 anevent which causes the two bead species to be brought into closeproximity in the presence of antibody leading to the generation ofluminescence which is detected on a Perkin Elmer reader (Fusion).

The ATP Radiometric ChK1 assay is carried out by incubation for 30minutes in the presence of 10 μM ATP containing 0.3 μCi ³³P-ATP persample and using ChKTide (peptide sequence KKKVSRSGLYRSPSMPENLNRPR) as asubstrate. Following acidification with 1% phosphoric acid and washingto remove unincorporated ATP, phosphorylation of the substrate isdetected and quantified by measurement of radioactivity incorporatedusing a Perkin Elmer Topcount.

The chk2 AlphaScreen assay is carried out for 30 minutes in the presenceof 30 μM ATP using biotinylated tyrosine hydroxylase (ser 40) peptide(Cell Signalling Technology, product #1132) as a substrate.Phosphorylation of the substrate is detected and quantified usingAlphaScreen technology. This consists of an anti-phospho-tyrosinehydroxylase (ser 40) peptide antibody (Cell Signalling technologyProduct #2791) and two AlphaScreen beads (Perkin Elmer), one productcoated with Protein A which binds the antibody Ig chain (Product6760137), and one coated with Streptavidin which binds the biotin on thebiotinylated tyrosine hydroxylase (ser 40) peptide (Product 6760002).Chk2 activity results in the production of phosphorylated tyrosinehydroxylase peptide an event which causes the two bead species to bebrought into close proximity in the presence of antibody leading to thegeneration of luminescence which is detected on a Perkin Elmer reader(Fusion).

The ATP Radiometric ChK2 assay is carried out by incubation for 30minutes in the presence of 30 μM ATP containing 0.3 μCi ³³P-ATP persample and using ChKTide (peptide sequence KKKVSRSGLYRSPSMPENLNRPR) as asubstrate. Following acidification with 1% phosphoric acid and washingto remove unincorporated ATP, phosphorylation of the substrate isdetected and quantified by measurement of radioactivity incorporatedusing a Perkin Elmer Topcount.

Test compounds are diluted in DMSO prior to addition to assay buffer,the final DMSO concentration in the assay is 1%.

The IC₅₀ is defined as the concentration at which a given test compoundachieved 50% inhibition of the control. IC₅₀ values are calculated usingthe XLfit software package (version 2.0.5).

Title compounds of EXAMPLES 1-119, 121-141, 143, 145-146, 148-171, 173,175-178, 180-181, 184, and 186-403 exhibited an IC₅₀ of less than 5 μMin the assays described in EXAMPLE i against chk1.

Example ii Cellular Assay (Checkpoint Abrogation)

Compounds are tested in a cellular assay using the human colorectaladenocarcinoma derived cell line HT-29 (ATCC HTB-38).

The cell line is maintained in DMEM/F12 (1:1) media (Invitrogen Gibco,#31331) supplemented with 10% FCS at 37° C. in a 5% CO₂ humidifiedincubator.

Cells are seeded in 96-well plates at 30,000 cells/well and after 24 hthey are exposed to 20 nM SN-38 in 0.4% DMSO. One column of 8 wells oneach plate was used to generate a maximum signal control. These cellsare treated with 0.4% DMSO without SN-38. Cells are grown for a further16 h, then the media containing DMSO plus or minus SN-38 is removed andreplaced with media containing 300 nM nocodazole alone (to determinebaseline) or in combination with ten concentrations of chk1 inhibitor(final DMSO concentration is 0.4%). Cells are grown for a further 24 h.The media is removed and replaced with 50 μl lysis buffer containingprotease inhibitors and phosphatase inhibitors. This buffer containsdetergent to bring about cellular disruption. Following completecellular disruption, 25 μl lysate is transferred to a MesoScale 96 well4-spot plate coated with an antibody to Histone H3 (MesoScale Discovery(MSD) Product K110EWA-3) which have been previously blocked with 3%bovine serum albumin in Tris buffered saline. Following the transfer oflysate to the MSD plate, Histone H3 in the lysate is captured on thecoated antibody by incubation at room temperature for 2 h. Following thecapture step the plate is washed and then incubated with an antibody tophosphorylated Histone H3 which is conjugated with a Sulfo-Tag. This taggives a signal when in proximity to the electrode on the base of the MSDplate. Binding the tagged antibody to the captured protein allowdetection on a MSD reader.

The EC₅₀ is defined as the concentration at which a given compoundachieves 50% decrease of the measured levels of phospho-Histone H3within the range of a normal sigmoidal dose response curve compared tothe signal generated by 300 nM nocodazole alone. EC₅₀ values arecalculated using the XLfit software package (version 2.0.5) or GraphpadPrism, (version 3.03) fitting a sigmoidal curve with a variable slope.

Title compounds of EXAMPLES 1, 4-7, 9-13, 15-30, 32-41, 43-46, 48-55,58-62, 64-77, 80, 84-90, 93-117, 119, 125, 127, 130-133, 135, 138, 157,160, 166, 176, 180, 186, 188, 190, 194-195, 198-209, 211-212, 214,216-282, 284-316, 319-322, 324-338, 343-344, 350-351, 353-362, 366, 368,370-389, 391-395, 397-402 exhibited an EC₅₀ of less than 10 μM in theassay described in EXAMPLE ii.

1. A method of inhibiting abnormal cell growth or treating ahyperproliferative disorder in a mammal comprising administering to saidmammal a therapeutically effective amount of a compound of formula (I),or a salt thereof:

X is CR² or N; Y is CR⁴ or N; Z is CR⁸ or N; provided that no more thanone of X, Y and Z is N at the same time; R² is H, halo, CN, CF₃, —OCF₃,OH, —NO₂, C₁-C₅ alkyl, —O(C₁-C₅ alkyl), —S(C₁-C₅ alkyl), or N(R²²)₂; R³is H, halo, CN, —O—R⁹, —N(R²²)—R⁹, —S(O)_(p)—R⁹, or R⁹; p is 0, 1 or 2;R⁴ is H, halo, CN, CF₃, —OCF₃, OH, —NO₂, —(CR¹⁴R¹⁵)_(n)C(═Y)OR¹¹,—(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹,—(CR¹⁴R¹⁵)_(n)S(O)_(p)R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y)R¹¹,—(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)OR¹¹, —(CR¹⁴R¹⁵)—NR¹²C(═Y′)NR¹¹R¹²,—(CR¹⁴R¹⁵)—NR¹²SO₂R¹¹, —(CR¹⁴R¹⁵)_(n)C(═Y′)R¹¹,—(CR¹⁴R¹⁵)_(n)OC(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)—S(O)₂NR¹¹R¹², alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein saidalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroarylare optionally substituted with one to four R¹³ groups; each n isindependently 0-5; R⁵ is H, halo, CN, CF₃, —OCF₃, OH, —NO₂,—(CR¹⁴R¹⁵)_(n)C(═Y′)OR¹¹, —(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹¹R¹²,—(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹,—(CR¹⁴R¹⁵)_(n)S(O)_(p)R¹¹, —(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)OR¹¹,(CR¹⁴R¹⁵)_(n)NR¹²C(═Y′)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)NR¹²SO₂R¹¹,—(CR¹⁴R¹⁵)_(n)OC(═Y′)R¹¹, —(CR¹⁴R¹⁵)_(n)OC(═Y′)NR¹¹R¹²;—(CR¹⁴R¹⁵)—S(O)₂NR¹¹R¹², alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl wherein the said alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substitutedwith one to four R¹³ groups; R⁶ is CN, —CF₃, —OCF₃, halo,—C(═Y′)NR¹¹R¹²; —OR¹¹, —OC(═Y′)_(R) ¹¹, —NR¹¹R¹²; NR¹²C(═Y′)R¹¹,—NR¹²C(═Y′)NR¹¹R¹²; NR¹²S(O)_(q)R¹¹; —SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹,—OC(═Y′)NR¹¹R¹², S(O)₂NR¹¹R¹², alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substitutedby one to four R¹³ groups; R⁸ is H, halo, CN, NO₂, N(R²²)₂, OH, O(C₁-C₃alkyl), or C₁-C₃ alkyl, wherein each said alkyl is optionallysubstituted with one to three fluoro groups; each R⁹ is independentlyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,wherein each member of R⁹ is independently substituted with one to threeR¹⁰ groups; each R¹⁰ is independently H, CN, —CF₃, —OCF₃, —NO₂, halo,R¹¹, —OR¹¹, —NR¹²C(═Y═)R¹¹, —NR¹²C(═NR¹²)R¹¹, —NR¹²S(O)_(q)R¹¹, —SR¹¹,—NR¹¹R¹², oxo, —C(═Y′)OR¹¹, —C(═Y′)NR¹¹R¹², —S(O)_(q)R¹¹, NR¹²C(Y′)OR¹¹,—NR¹²C(═Y′)NR¹¹R¹²; —OC(═Y′)R¹¹, —OC(═Y′)NR¹¹R¹², or —S(O)₂NR¹¹R¹²; eachq independently is 1 or 2; R¹¹ and R¹² are independently H, alkyl,cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl,cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substitutedwith one to four R¹³ groups, wherein two geminal R¹³ groups areoptionally taken together with the atom to which they are attached toform a 3-6 membered ring having additional 0-2 heteroatoms selected fromO, S, and N, said ring being optionally substituted with one to four R¹⁸groups; R¹¹ and R¹² are optionally taken together with the attached Natom to form a 4-7 membered ring having additional 0-2 heteroatomsselected from O, S, and N, said ring being optionally substituted withone to four R¹³ groups; each R¹³ is independently halo, CN, CF₃, —OCF₃,—NO₂, oxo, —(CR¹⁴R¹⁵)_(n)C(═Y′)R¹⁶, —(CR¹⁴R¹⁵)_(n)C(═Y′)OR¹⁶,—(CR¹⁴R¹⁵)_(n)C(═Y′)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)OR¹⁶,—(CR¹⁴R¹⁵)_(n)SR¹⁶, —(CR¹⁴R¹⁵)_(n)NR¹⁶C(═Y)R¹⁷,—(CR¹⁴R¹⁵)_(n)NR¹⁶C(═Y′)OR¹⁷, —(CR¹⁴R¹⁵)_(n)NR¹⁷C(═Y′)NR¹⁶R¹⁷,—(CR¹⁴R¹⁵)_(n)NR¹⁷SO₂R¹⁶, —(CR¹⁴R¹⁵)_(n)OC(═Y′)R¹⁶,—(CR¹⁴R¹⁵)_(n)C(═Y)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)S(O)R¹⁶, —(CR¹⁴R¹⁵)—S(O)₂R¹⁶,—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷, or R¹⁶; R¹⁴ and R¹⁵ are independentlyselected from H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl areoptionally substituted with one to four R¹⁸ groups; R¹⁶ and R¹⁷ areindependently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl areoptionally substituted with one to four R¹⁸ groups; R¹⁶ and R¹⁷ areoptionally taken together with the attached N atom to form a 5-6membered ring having additional 0-2 heteroatoms selected from O, S, andN, said ring being optionally substituted with one to four R¹⁸ groups;each R¹⁸ is independently H, alkyl, cycloalkyl, heterocyclyl, aryl,heteroaryl, halo, CN, CF₃, —OCF₃, —NO₂, oxo, —(CR¹⁹R²⁰)_(n)C(═Y′)R²³,—(CR¹⁹R²⁰)_(n) C(═Y′)OR²³, —(CR¹⁹R²⁰)_(n) C(═Y′)NR²³R²⁴,—(CR¹⁹R²⁰)_(n)NR²³R²⁴, —(CR¹⁹R²⁰)_(n)OR²³, —(CR¹⁹R²⁰)_(n)—SR²³,—(CR¹⁹R²⁰)_(n)NR²⁴C(═Y ‘)R²³, —(CR¹⁹R²⁰)_(n)NR²⁴C(═Y’)OR²³,—(CR¹⁹R²⁰)_(n)NR²²C(═Y′)NR²³R²⁴, —(CR¹⁹R²⁰)_(n)NR²⁴SO₂R²³,—(CR¹⁹R²⁰)_(n)OC(═Y′)R²³, —(CR¹⁹R²⁰)_(n) OC(═Y′)NR²³R²⁴,—(CR¹⁹R²⁰)_(n)S(O)R²³, —(CR¹⁹R²⁰)_(n)S(O)₂R²³, or—(CR¹⁹R²⁰)_(n)S(O)₂NR²³R²⁴, wherein said alkyl, cycloalkyl,heterocyclyl, aryl, and heteroaryl are optionally substituted with oneto four R²¹ groups; R¹⁹ and R²⁰ are independently H, alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one tofour R²⁵ groups; R²³ and R²⁴ are independently H, alkyl, cycloalkyl,heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl,heterocyclyl, aryl and heteroaryl are optionally substituted with one tofour R²¹ groups; R²³ and R²⁴ are optionally taken together with theattached N atom to form a 5-6 membered ring having additional 0-2heteroatoms selected from O, S, and N, said ring being optionallysubstituted with one to four R²¹ groups; each R²¹ is independently H,alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN, CF₃, —OCF₃,—NO₂, oxo, —C(═Y)R²⁵, —C(═Y′)OR²⁵, —C(═Y′)NR²⁵R²⁶, —NR²⁵R²⁶, —OR²⁵,—SR²⁵, —NR²⁶C(═Y′)R²⁵, —NR²⁶C(═Y′)OR²⁵, —NR²²C(═Y′)NR²⁵R²⁶, NR²⁶SO₂R²⁵,—OC(═Y′)R²⁵, —OC(═Y′)NR²⁵R²⁶, —S(O)R²⁵, —S(O)₂R²⁵, or —S(O)₂NR²⁵R²⁶,wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl areoptionally substituted with one to four R²⁵ groups; each R²⁵ and R²⁶ isindependently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one to four groups selected from halo, —CN,—OCF₃, —CF₃, —NO₂, —C₁-C₆ alkyl, —OH, oxo, —SH, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —SO₂(C₁-C₆alkyl), —CO₂H, —CO₂(C₁-C₆ alkyl), —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl),—C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆ alkyl), —NHC(O)(C₁-C₆alkyl), —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂,—SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆ alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆alkyl), —OC(O)N(C₁-C₆ alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆alkyl)₂, —NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆alkyl), and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆ alkyl); R²⁵ and R²⁶ areoptionally taken together with the attached N atom to form a 5-6membered ring having additional 0-2 heteroatoms selected from O, S, andN, said ring being optionally substituted with one to four groupsselected from halo, —CN, —OCF₃, CF₃, —NO₂, —C₁-C₆ alkyl, —OH, oxo, —SH,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —SO₂(C₁-C₆ alkyl), —CO₂H, —CO₂(C₁-C₆ alkyl), —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), —C(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)C(O)(C₁-C₆alkyl), —NHC(O)(C₁-C₆ alkyl), —NHSO₂(C₁-C₆ alkyl), —N(C₁-C₆alkyl)SO₂(C₁-C₆ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₆ alkyl), —SO₂N(C₁-C₆alkyl)₂, —OC(O)NH₂, —OC(O)NH(C₁-C₆ alkyl), —OC(O)N(C₁-C₆ alkyl)₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)C(O)NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)C(O)N(C₁-C₆ alkyl)₂,—NHC(O)NH(C₁-C₆ alkyl), —NHC(O)N(C₁-C₆ alkyl)₂, —NHC(O)O(C₁-C₆ alkyl),and —N(C₁-C₆ alkyl)C(O)O(C₁-C₆ alkyl); Y′ is independently O, NR²², orS; and each R²² is independently H or C₁-C₅ alkyl.
 2. The method ofclaim 1, wherein the compounds of formula (I) are those wherein X isCR².
 3. The method of claim 1, wherein the compounds of formula (I) arethose wherein R² is H.
 4. The method of claim 1, wherein the compoundsof formula (I) are those wherein Y is CR⁴.
 5. The method of claim 1,wherein the compounds of formula (I) are those wherein R⁴ is H.
 6. Themethod of claim 1, wherein the compounds of formula (I) are thosewherein Z is CR⁸.
 7. The method of claim 1, wherein the compounds offormula (I) are those wherein R⁸ is H.
 8. The method of claim 1, whereinthe compounds of formula (I) are those wherein R³ is Br.
 9. The methodof claim 1, wherein the compounds of formula (I) are those wherein R³ isH.
 10. The method of claim 1, wherein the compounds of formula (I) arethose wherein R³ is R⁹.
 11. The method of claim 1, wherein the compoundsof formula (I) are those wherein R⁹ is C₁-C₆ alkyl, C₂-C₃ alkynyl, C₆aryl, or 5-6 membered monocyclic or 8-10-membered bicyclic heteroarylhaving 1 to 2 ring atoms selected from N, O and S; and wherein eachmember of R⁹ is independently substituted with one to two R¹⁰ groups.12. The method of claim 1, wherein the compounds of formula (I) arethose wherein R⁹ is isopropyl, propynyl, phenyl, pyrazolyl, furanyl,thienyl, pyridyl, imidazolyl, pyrimidinyl, benzothienyl, thiazolyl,tetrahydrothienopyridinyl, tetrahydrothiazolopyridinyl, isothiazolyl,tetrahydropyridinyl, tetrahydroisoquinolinyl, triazolyl,dihydrobenzodioxinyl, dihydroindolyl, oxazolyl, ortetrahydrobenzothienyl, wherein each member of R⁹ is independentlysubstituted with one to two R¹⁰ groups.
 13. The method of claim 1,wherein the compounds of formula (I) are those wherein R¹⁰ is halo, R¹¹,—OR¹¹, CN, —CF₃, —OCF₃, NR¹²C(═O)R¹¹, —NR¹²S(O)_(q)R¹¹, —SR¹¹, —NR¹¹R¹²,—C(═O)NR¹¹R¹², oxo, —S(O)_(q)R¹¹, —S(O)₂NR¹¹R¹², or —C(═O)OR¹¹, whereinR¹¹ and R¹² are optionally taken together with the attached N atom toform a 4-7 membered ring having additional 0-2 heteroatoms selected fromO, S, and N, said ring being optionally substituted with one to four R¹³groups.
 14. The method of claim 1, wherein the compounds of formula (I)are those wherein R¹⁰ is R¹¹.
 15. The method of claim 1, wherein thecompounds of formula (I) are those wherein R¹¹ is C₁-C₆ alkyl, or 4-6membered monocyclic or 8-10 membered bicyclic heterocyclyl having 1 to 2heteroatoms selected from N and O, wherein said alkyl and heterocyclylare optionally substituted with one to four R¹³ groups, wherein twogeminal R¹³ groups are optionally taken together with the atom to whichthey are attached to form a six-membered ring having 0-2 heteroatomselected from O, S, and N, said ring being optionally substituted withone to four R¹⁸ groups.
 16. The method of claim 1, wherein the compoundsof formula (I) are those wherein R¹¹ is C₁-C₆ alkyl, wherein alkyl isoptionally substituted with one to two R¹³ groups and wherein each R¹³is independently halo, CN, CF₃, —OCF₃, oxo, —(CR¹⁴R¹⁵)_(n)C(O)OR¹⁶,—(CR¹⁴R¹⁵)_(n)C(O)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)OR¹⁶,—(CR¹⁴R¹⁵)_(n)NR¹⁶C(O)R¹⁷, —(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷, or R¹⁶.
 17. Themethod of claim 1, wherein the compounds of formula (I) are thosewherein R¹¹ is 4-6 membered monocyclic or 8-10 membered bicyclicheterocyclyl having 1 to 2 heteroatoms selected from N and O, whereinsaid alkyl and heterocyclyl are optionally substituted with one to twoR¹³ groups and wherein each R¹³ is independently halo, CN, CF₃, —OCF₃,oxo, (CR¹⁴R¹⁵)_(n)C(O)OR¹⁶, —(CR¹⁴R¹⁵)_(n)C(O)NR¹⁶R¹⁷,—(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)OR¹⁶, —(CR¹⁴R¹⁵)_(n)NR¹⁶C(O)R¹⁷,—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷, or R¹⁶.
 18. The method of claim 1, whereinthe compounds of formula (I) are those wherein R¹⁰ is —OR¹¹.
 19. Themethod of claim 1, wherein the compounds of formula (I) are thosewherein R¹¹ is H, C₁-C₄ alkyl, or 4-6 membered monocyclic or 8-10membered bicyclic heterocyclyl having 1 to 2 nitrogen atoms, whereinsaid alkyl or heterocyclyl is optionally substituted with one to two R¹³groups, wherein each R¹³ is independently halo, CN, CF₃, —OCF₃, oxo,—(CR¹⁴R¹⁵)—C(O)OR¹⁶, (CR¹⁴R¹⁵)_(n)C(O)NR¹⁶R¹⁷, —(CR¹⁴R¹⁵)_(n)NR¹⁶R¹⁷,—(CR¹⁴R¹⁵)_(n)OR¹⁶, —(CR¹⁴R¹⁵)_(n)NR¹⁶C(O)R¹⁷,—(CR¹⁴R¹⁵)_(n)S(O)₂NR¹⁶R¹⁷or R¹⁶.
 20. The method of claim 1, wherein thecompounds of formula (I) are those wherein R⁵ is H.
 21. The method ofclaim 1, wherein the compounds of formula (I) are those wherein R⁵ is—(CR¹⁴R¹⁵)_(n)C(O)NR¹¹R¹², (CR¹⁴R¹⁵)_(n)NR¹²C(O)R¹¹,—(CR14R¹⁵)_(n)NR¹¹R¹², —(CR¹⁴R¹⁵)_(n)OR¹¹, C₁-C₆ alkyl, or 4-6 memberedmonocyclic or 7-10 membered bicyclic heterocyclyl having 1 to 2 nitrogenatoms, wherein said alkyl or heterocyclyl is optionally substituted withone to two R¹³ groups; wherein R¹⁴ and R¹⁵ are H; n is 0-2; each R¹¹ isindependently H, C₁-C₄ alkyl, or 5-6 membered monocyclic heterocyclylhaving 1 to 2 nitrogen atoms, wherein said alkyl or heterocyclyl isoptionally substituted with one to two R¹³ groups; and R¹³ is OH,O(C₁-C₃ alkyl), or C₁-C₃ alkyl.
 22. The method of claim 1, wherein thecompounds of formula (I) are those wherein R⁶ is CN, halo, —C(O)NR¹¹R¹²,—OR¹¹, —NR¹¹R¹², —NR¹²C(O)R¹¹, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, 5-6membered heterocyclyl having 1 to 2 heteroatoms, C₆ aryl, or 5-6membered heteroaryl having 1 to 2 heteroatoms; wherein said alkyl issubstituted with one to two R¹³ groups except H; and said cycloalkyl,aryl, heterocyclyl or heteroaryl is optionally substituted by one to twoR¹³ groups; wherein heteroatoms are selected from N, O and S; whereineach R¹² is H or C₁-C₃ alkyl and each R¹¹ is independently H or C₁-C₃alkyl optionally substituted by one to two R¹³ groups.
 23. The method ofclaim 1, wherein the compounds of formula (I) are those wherein R⁶ isCN.
 24. (canceled)
 25. The method of claim 1, wherein the compounds offormula (I) are selected from the group consisting of:


26. (canceled)
 27. (canceled)
 28. (canceled)
 29. (canceled)
 30. Themethod of any one of claims 1 to 25 and 33 to 44 wherein thehyperproliferative disorder is cancer in a mammal.
 31. The method ofclaim 30, wherein cancer is selected from breast cancer, prostatecancer, pancreatic cancer, colorectal cancer, ovarian cancer, non-smallcell lung cancer, malignant brain tumors, sarcomas, melanoma, lymphoma,myelomas leukemia and acute myelogenous leukemia (AML).
 32. (canceled)33. The method of claim 1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 34. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 35. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 36. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 37. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 38. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 39. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 40. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 41. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 42. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 43. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 44. The method of claim1, wherein the compound of formula (I) is:

or a pharmaceutically acceptable salt thereof.
 45. The method of claim1, comprising administering a second therapeutic agent selected from thegroup consisting of: Erlotinib (TARCEVA®, Genentech/OSI Pharm.),Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®,AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis),Imatinib mesylate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis),Oxaliplatin (Eloxatin®, Sanofi), Leucovorin, Rapamycin (Sirolimus,RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline),Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), andGefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylsulfonates comprising busulfan, improsulfan and piposulfan; aziridinescomprising benzodopa, carboquone, meturedopa, and uredopa; ethyleniminesand methylamelamines comprising altretamine, triethylenemelamine,triethylenephosphoramide, triethylenethiophosphoramide andtrimethylomelamine; acetogenins comprising bullatacin and bullatacinone;bryostatin; callystatin; CC-1065 comprising its adozelesin, carzelesinand bizelesin synthetic analogs; cryptophycins comprising cryptophycin 1and cryptophycin 8; dolastatin; duocarmycin comprising the syntheticanalogs, KW-2189 and CB1-TM1; eleutherobin; pancratistatin; asarcodictyin; spongistatin; folic acid analogs comprising denopterin,methotrexate, pteropterin, and trimetrexate; purine analogs comprisingfludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidineanalogs comprising ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine;androgens comprising calusterone, dromostanolone propionate,epitiostanol, mepitiostane, and testolactone; anti-adrenals comprisingaminoglutethimide, mitotane, and trilostane; folic acid replenishercomprising frolinic acid; aceglatone; aldophosphamide glycoside;aminolevulinic acid; eniluracil; bestrabucil; bisantrene; edatraxate;defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate;an epothilone; etoglucid; gallium nitrate; lentinan; lonidainine;maytansinoids comprising maytansine and ansamitocins; mitoguazone;mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet;pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide;procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene,Oreg.); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid;triaziquone; 2,2′,2″-trichlorotriethylamine; trichothecenes comprisingT-2 toxin, verracurin A, roridin A and anguidine); urethan; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); chloranmbucil; 6-thioguanine; mercaptopurine;ifosfamide; mitoxantrone; novantrone; edatrexate; daunomycin;aminopterin; capecitabine (XELODA®); ibandronate; CPT-11;difluoromethylornithine (DMFO); anti-hormonal agents that act toregulate or inhibit hormone action on tumors comprising anti-estrogensand selective estrogen receptor modulators (SERMs), comprising tamoxifencomprising NOLVADEX®; tamoxifen citrate, raloxifene, droloxifene,4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, andFARESTON® (toremifine citrate); aromatase inhibitors that inhibit theenzyme aromatase, which regulates estrogen production in the adrenalglands, comprising 4(5)-imidazoles, aminoglutethimide, MEGASE®(megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie,fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), andARIMIDEX® (anastrozole; AstraZeneca); anti-androgens comprisingflutamide, nilutamide, bicalutamide, leuprolide, and goserelin;troxacitabine comprising 1,3-dioxolane nucleoside cytosine analogs;protein kinase inhibitors; lipid kinase inhibitors; antisenseoligonucleotides, comprising those which inhibit expression of genes insignaling pathways implicated in aberrant cell proliferation, comprisingPKC-alpha, Ralf and H-Ras; ribozymes comprising VEGF expressioninhibitors comprising ANGIOZYME® and HER2 expression inhibitors;vaccines comprising gene therapy vaccines, comprising ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitorcomprising LURTOTECAN®; ABARELIX® rmRH; anti-angiogenic agentscomprising bevacizumab (AVASTIN®, Genentech); inhibitors of MEK,comprising MAP kinase kinase, comprising XL518 (Exelixis, Inc.) andAZD6244 (Astrazeneca); inhibitors of Raf, comprising XL281 (Exelixis,Inc.), PLX4032 (Plexxikon), and ISIS5132 (Isis Pharmaceuticals);inhibitors of mTor comprising rapamycin, AP23573 (AriadPharmaceuticals), temsirolimus (Wyeth Pharmaceuticals) and RAD001(Novartis); inhibitors of PI3K (phosphoinositide-3 kinase), comprisingSF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3Kinhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.), andGDC-0941 (Genentech); inhibitors of cMet, comprising PHA665752 (Pfizer),XL-880 (Exelixis, Inc.), ARQ-197 (ArQule), and CE-355621; DNA damagingagent comprising thiotepa and CYTOXAN® cyclosphosphamide; alkylatingagents comprising cis-platin; carboplatin; cyclophosphamide; nitrogenmustards comprising chlorambucil, chlornaphazine, chlorophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; busulphan; nitrosoureas comprisingcarmustine, chlorozotocin, fotemustine, lomustine, nimustine,ranimnustine and temozolomide; antimetabolites comprising antifolatescomprising fluoropyrimidines like 5-fluorouracil (5-FU) and tegafur,raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and GEMZAR®(gemcitabine); antitumour antibiotics comprising enediyne antibioticscomprising calicheamicin comprising calicheamicin gamma1I andcalicheamicin omegaI1; anthracyclines comprising adriamycin; dynemicin,comprising dynemicin A; bisphosphonates, comprising clodronate; anesperamicin; neocarzinostatin chromophore and related chromoproteinenediyne antibiotic chromophores, aclacinomysins, actinomycin,authramycin, azaserine, bleomycins, cactinomycin, carabicin,caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin),morpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins comprising mitomycin C,mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin,puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,tubercidin, ubenimex, zinostatin, and zorubicin; antimitotic agentscomprising vinca alkaloids like vincristine, vinblastine, vindesine andNAVELBINE® (vinorelbine) and taxoids like taxoids, e.g., TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel, and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony,France); topoisomerase inhibitors comprising RFS 2000,epipodophyllotoxins like etoposide and teniposide, amsacrine, acamptothecin comprising the synthetic analog topotecan, and irinotecanand SN-38 and cytodifferentiating agents comprising retinoids comprisingall-trans retinoic acid, 13-cis retinoic acid and fenretinide; an agentthat modulates the apoptotic response comprising inhibitors of IAP(inhibitor of apoptosis proteins) comprising AEG40826 (AegeraTherapeutics); and inhibitors of bcl-2 comprising GX15-070 (Gemin XBiotechnologies), CND0103 (Apogossypol; Coronado Biosciences), HA14-1(ethyl2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate),AT101 (Ascenta Therapeutics), ABT-737 and ABT-263 (Abbott); andpharmaceutically acceptable salts thereof.
 46. The method of claim 45,wherein the second therapeutic agent is selected from the groupconsisting of Gemcitabine, Irinotecan, SN-38, arabinoside (“Ara-C”) anda topoisomerase inhibitor 1 or
 2. 47. A method of treating cancerselected from the group consisting of breast cancer, colorectal cancer,prostate cancer, pancreatic cancer, ovarian cancer, non-small cell lungcancer, malignant brain tumors, sarcomas, melanoma, lymphoma, myelomas,leukemia and acute myelogenous leukemia (AML) in a mammal comprisingadministering to said mammal a therapeutically effective amount of acompound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof and a secondchemotherapeutic agent selected from the group consisting ofGemcitabine, Irinotecan, SN-38, arabinoside (“Ara-C”) and atopoisomerase inhibitor 1 or 2.